Thiazolyl inhibitors of Tec family tyrosine kinases

ABSTRACT

Novel thiazolyl compounds and salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds in the treatment of Tec family tyrosine kinase-associated disorders such as cancer, immunologic disorders and allergic disorders.

This application is a Divisional Application of prior application Ser.No. 10/027,982 filed on Dec. 20, 2001, now U.S. Pat. No. 6,706,717,which claims priority to U.S. Provisional Application Ser. No.60/257,830 filed Dec. 21, 2000, the entirety of which is incorporatedherein by reference.

FIELD OF THE INVENTION

The present invention provides for thiazolyl compounds useful asinhibitors of Tec family tyrosine kinases (especially inhibitors of Emt)and to pharmaceutical compositions containing such compounds. Thepresent invention further provides for methods of using such compoundsas immunosuppressive, anti-inflammatory, anti-allergic, and anti-canceragents.

BACKGROUND OF THE INVENTION

The present invention relates to inhibitors of the Tec family tyrosinekinases, and particularly, inhibitors of Emt. The Tec family kinasesinclude Emt [expressed mainly in T cells; Gibson, S. et al., Blood 82,1561-1572 (1993)], Txk [T-cell expressed kinase; Haire, R. N. et al.,Hum. Mol. Genet. 3, 897-901 (1994)1, Tec [tyrosine kinase expressed inhepatocellular carcinoma cells; Mano et al., Oncogene 5, 1781-1786(1990)], Btk [Bruton's tyrosine kinase; Vetrie, D. et al., Nature 361,226-233, (1993)], and Bmx [bone marrow kinase, X-linked; Tamagnon, L. etal., Oncogene 9, 3683-3688 (1994)].

Mammalian immunity relies on the activation of T cells upon antigenpresentation. The molecular mechanisms of T cell activation areinitiated by the sequential activation of three distinct classes ofnon-receptor protein tyrosine kinases (PTK) following the engagement ofthe T cell antigen receptor (TCR). These three classes of PTK are theSrc family kinases (Lck and Lyn), the Syk family kinases (ZAP-70 andSyk), and the Tec family kinases (Emt, Txk, and Tec). Inhibition of oneor more of these kinases will impede the initiation signals and block Tcell activation following antigen presentation. Thus, small molecularweight inhibitors of these kinases can be applied to treat the diseasesthat are associated with unwanted T cell activation.

Emt, also known as Itk (Interleukin-2-inducible T cell kinases) or Tsk(T-cell-specific tyrosine kinase), is expressed solely in T, naturalkiller, and mast cells. Emt is tyrosine-phosphorylated and activated inresponse to cross-linking of TCR, CD28, or CD2; and has been implicatedin thymocyte development and the activation of T cells through TCR andCD28 engagement. Inside the cells, Emt is regulated by membranerecruitment followed by LCk phosphorylation and autophosphorylation. Emtis recruited to the membrane rafts for LCk phosphorylation through theinteraction between the pleckstrin homology (PH) domain of Emt and themembrane lipid, phosphotidylinositol (3,4,5)-triphosphate [Bunnell etal., J. Biol. Chem. 275, 2219-2230 (2000)].

Gene knockout studies reveal that mice lacking Emt have decreasednumbers of mature thymocytes, especially CD4+ T cells. The T cellsisolated from such mice are compromised in their proliferative responseto allogeneic MHC stimulation, and to anti-TCR/CD3 cross-linking [LiaoX. C. and Littman, D. R., Immunity 3, 757-769 (1995)]. These T cellsalso exhibit defective PLCγ1 tyrosine phosphorylation, inositoltriphosphate production, Ca²⁺ moblization, and cytokine production (suchas IL-2 and IFNγ) in response to TCR cross-linking [Schaeffer, E. M. etal., Science 284, 638-641 (1999)]. This genetic evidence indicates thatEmt activity plays a requisite role in TCR signal transduction; andselective inhibition of Emt should have immunosuppressive,anti-inflammatory, and anti-proliferative effects. In addition,Emt-deficient mice are unable to establish functional Th2 cells (theIL-4 producing cells) and such mice are unable to clear parasiticinfections depending upon a Th2 response [Fowell, D. J. et al., Immunity11, 399-409 (1999)]. This observation also suggests that Emt may be anattractive target for modulating dysregulated allergic pathways mediatedby Th2 cells.

SUMMARY OF THE INVENTION

The present invention provides thiazolyl compounds of the followingformula I and salts thereof for use as Emt tyrosine kinase inhibitors:

where

-   Q₁ is thiazolyl;-   Q₂ is aryl or heteroaryl optionally independently substituted with    one or more (preferably one to three) substituents R_(1a);-   Z is    -   (1) —O—,    -   (2) —S—,    -   (3) —NR₄—,    -   (4) —CR₄R₅—,    -   (5) —CR₄R₅—O—CR_(4a)R_(5a)—,    -   (6) —CR₄R₅—NR_(4b)—CR_(4a)R_(5a)—,    -   (7) —CR₄R₅—S—CR_(4a)R_(5a)—,    -   (8) —CR₄R₅—O—,    -   (9) —O—CR₄R₅—,    -   (10) —CR₄R₅—NR_(4b)—,    -   (11) —NR_(4b)—CR₄R₅—,    -   (12) —CR₄R₅—S—,    -   (13) —S—CR₄R₅—,    -   (14) —S(O)_(q)— where q is 1 or 2,    -   (15) —CR₄R₅—S(O)_(q)—, or    -   (16) —S(O)_(q)—CR₄R₅—;-   R₁ and R_(1a), are independently    -   (I) hydrogen or R₆,    -   (2) —OH or —OR₆,    -   (3) —SH or —SR₆,    -   (4) —C(O)_(q)H, —C(O)_(q)R₆, or —O—C(O)_(q)R₆,    -   (5) —O3H or —(O)_(q)R₆,    -   (6) halo,    -   (7) cyano,    -   (8) nitro,    -   (9) -Z₄-NR₇R₈,    -   (10) -Z₄-N(R₉)-Z₅-NR₁₀R₁₁,    -   (11) -Z₄-N(R₁₂)-Z₅-R₆, or    -   (12) —P(O)(OR₆)₂;-   R₂ and R₃ are each independently H, -Z₄-R_(6a), or -Z₄-NR_(7a)R_(8a)-   R₄, R_(4a), R_(4b), R₅ and R_(5a) are each independently hydrogen,    alkyl, aryl, aralkyl, cycloalkyl, or heteroarylalkyl;-   R₆, R_(6a), R_(6b) and R_(6c) are independently alkyl, alkenyl,    alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,    cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl,    each of which is unsubstituted or substituted with Z₁, Z₂ and one or    more (preferably, one or two) groups Z₃,-   R₇, R_(7a), R₈, R_(8a), R₉, R₁₀, R₁₁ and R₁₂    -   (1) are each independently hydrogen, or -ZR_(6b); or    -   (2) R₇ and R₈ or R_(7a) and R_(8a) may together be alkylene,        alkenylene, or heteroalkylene, completing a 3- to 8-membered        saturated or unsaturated ring with the nitrogen atom to which        they are attached, which ring is unsubstituted or substituted        with Z₁, Z₂ and one or more groups Z₃, or    -   (3) any two of R₉, R₁₀ and R₁₁ may together be alkylene,        alkenylene or heteroalkylene completing a 3- to 8-membered        saturated or unsaturated ring together with the nitrogen atoms        to which they are attached, which ring is unsubstituted or        substituted with one or more Z₁, Z₂ and Z₃;-   Z₁, Z₂ and Z₃ are each independently    -   (1) hydrogen or Z₆,    -   (2) —H or —OZ₆,    -   (3) —SH or —SZ₆,    -   (4) —C(O)_(q)H, —C(O)_(q)Z₆, or O—C(O)_(q)Z₆,    -   (5) —O₃H, —S(O)_(q)Z₆, or S(O)_(q)N(Z₉)Z₆,    -   (6) halo,    -   (7) cyano,    -   (8) nitro,    -   (9) -Z₄-NZ₇Z₈,    -   (10) -Z₄-N(Z₉)-Z₅-NZ₇Z₈,    -   (11) -Z₄-N(Z₁₀)-Z₅-Z₆,    -   (12) -Z₄-N(Z₁₀)-Z₅-H,    -   (13) oxo,    -   (14) any two of Z₁, Z₂, and Z₃ on a given substituent may        together be alkylene or alkenylene completing a 3- to 8-membered        saturated or unsaturated ring together with the atoms to which        they are attached; or    -   (15) any two of Z₁, Z₂, and Z₃ on a given substituent may        together be —O—(CH₂)_(q)—O—;-   Z₄ and Z₅ are each independently    -   (1) a single bond,    -   (2) -Z₁₁-S(O)_(q)-Z₁₂-;    -   (3) -Z₁₁-C(O)-Z₁₂-;    -   (4) -Z₁₁-C(S)-Z₁₂-;    -   (5) -Z₁₁-O-Z₁₂-;    -   (6) -Z₁₁-S-Z₁₂-;    -   (7) -Z₁₁-O—C(O)-Z₁₂-;    -   (8) -Z₁₁C—(O)—O-Z₁₂-; or    -   (9) alkyl-   Z₆ and Z_(6a) are independently    -   (i) alkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,        cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl,        aryl, aralkyl, alkylaryl, cycloalkylalryl, heterocyclo, or        heterocycloalkyl;    -   (ii) a group (i) which is itself substituted by one or more of        the same or different groups (i); or    -   (iii) a group (i) or (ii) which is independently substituted by        one or more (preferably 1 to 3) of the groups (2) to (15) of the        definition of Z₁;-   Z₇, Z₈, Z₉ and Z₁₀    -   (1) are each independently hydrogen or -Z₄-Z_(6a);    -   (2) Z₇ and Z₈ may together be alkylene, alkenylene, or        heteroalkylene completing a 3- to 8-membered saturated or        unsaturated ring together with the atoms to which they are        attached, which ring is unsubstituted or substituted with one or        more Z₁, Z₂ and Z₃, or    -   (3) Z₇ or Z₈, together with Z₉, may be alkylene, alkenylene, or        heteroalkylene completing a 3- to 8-membered saturated or        unsaturated ring together with the nitrogen atoms to which they        are attached, which ring is unsubstituted or substituted with        one or more Z₁, Z₂ and Z₃;-   Z₁₁ and Z₁₂ are each independently    -   (1) a single bond,    -   (2) alkylene,    -   (3) alkenylene, or    -   (4) alkynylene.

DETAILED DESCRIPTION OF THE INVENTION

The following are definitions of terms used in this specification. Theinitial definition provided for a group or term herein applies to thatgroup or term throughout the present specification, individually or aspart of another group, unless otherwise indicated.

The terms “alk” or “alkyl” refer to straight or branched chainhydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbonatoms. The expression “lower alkyl” refers to alkyl groups of 1 to 4carbon atoms.

The term “alkenyl” refers to straight or branched chain hydrocarbongroups of 2 to 10, preferably 2 to 4, carbon atoms having at least onedouble bond. Where an alkenyl group is bonded to a nitrogen atom, it ispreferred that such group not be bonded directly through a carbonbearing a double bond.

The term “alkynyl” refers to straight or branched chain hydrocarbongroups of 2 to 10, preferably 2 to 4, carbon atoms having at least onetriple bond. Where an alkynyl group is bonded to a nitrogen atom, it ispreferred that such group not be bonded directly through a carbonbearing a triple bond.

The term “alkylene” refers to a straight chain bridge of 1 to 5 carbonatoms connected by single bonds (e.g., —(CH2)_(x)— wherein x is 1 to 5),which may be substituted with 1 to 3 lower alkyl groups.

The term “alkenylene” refers to a straight chain bridge of 2 to 5 carbonatoms having one or two double bonds that is connected by single bondsand may be substituted with 1 to 3 lower alkyl groups. Exemplaryalkenylene groups are —CH═CH—CH═CH—, —CH₂—CH═CH—, —CH₂—CH—CH—CH₂—,—C(CH₃)₂CH═CH— and —CH(C₂H₅)—CH═CH—.

The term “alkynylene” refers to a straight chain bridge of 2 to 5 carbonatoms that has a triple bond therein, is connected by single bonds, andmay be substituted with 1 to 3 lower alkyl groups. Exemplary alkynylenegroups are —C≡C—, —CH₂—C≡C—, —CH(CH₃)—C≡C— and —C≡C—CH(C₂H₅)CH₂—.

The term “heteroalkylene” refers to alkylene or alkenylene groupscontaining one or more heteroatoms N, O or S.

The terms “ar” or “aryl” refer to aromatic cyclic groups (for example 6membered monocyclic, 10 membered bicyclic or 14 membered tricyclic ringsystems) which contain 6 to 14 carbon atoms. Exemplary aryl groupsinclude phenyl, naphthyl, biphenyl and anthracene.

The terms “cycloalkyl” refers to saturated or partially unsaturated(containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl,containing a total of 3 to 20 carbons forming the rings, preferably 3 to7 carbons, forming the ring and which may be fused to 1 or 2 aromatic orheterocyclo rings, which include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl,cyclohexenyl,

The terms “halogen” and “halo” refer to fluorine, chlorine, bromine andiodine.

The terms “heterocycle”, “heterocyclic” or “heterocyclo” refer to fullysaturated or unsaturated, including aromatic (i.e. “heteroaryl”) cyclicgroups, for example, 4 to 7 membered monocyclic, 7 to 11 memberedbicyclic, or 10 to 15 membered tricyclic ring systems, which have atleast one heteroatom in at least one carbon atom-containing ring. Eachring of the heterocyclic group containing a heteroatom may have 1, 2, 3or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/orsulfur atoms, where the nitrogen and sulfur heteroatoms may optionallybe oxidized and the nitrogen heteroatoms may optionally be quaternized.The heterocyclic group may be attached at any heteroatom or carbon atomof the ring or ring system.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl,pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl,imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl,thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl,furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane andtetrahydro-1,1-dioxothienyl, triazolyl, triazinyl, 5-tetrazolyl,

and the like.

Exemplary bicyclic heterocyclic groups include indolyl, benzothiazolyl,benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl,tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (suchas furo[2,3-c]pyridinyl, furo[3,2-b)pyridinyl] or furo[2,3-b]pyridinyl),dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxoquinazolinyl), tetrahydroquinolinyl

and the like.

Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl,phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

The term “heteroaryl” refers to a 5- or 6- membered aromatic ring whichincludes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygen or sulfur,and such rings fused to an aryl, cycloalkyl, or heterocyclo ring (e.g.benzothiophenyl, indolyl), and includes possible N-oxides, such as

and the like.

Where q is 1 or 2, “—C(O)_(q)H” denotes —C(O)—H or —C(O)—OH;“—C(O)_(q)R₆” or “—C(O)_(q)Z₆” denote, respectively, —C(O)—R₆ or—C(O)—OR₆, or —C(O)-Z₆ or —C(O)—OZ₆; “—O—C(O)_(q)R₆” or “O—C(O)_(q)Z₆”denote, respectively, —O—C(O)—R₆ or —C(O)—OR₆, or —O—C(O)-Z₆ or—O—C(O)—OZ₆; and “—S(O)_(q)R₆” or “—S(O)⁴Z₆” denote, respectively,—SO—R₆ or —SO₂—R₆, or —SO-Z₆ or —SO₂-Z₆.

Compounds of the formula I may in some cases form salts which are alsowithin the scope of this invention. Reference to a compound of theformula I herein is understood to include reference to salts thereof,unless otherwise indicated. The term “salt(s)”, as employed herein,denotes acidic and/or basic salts formed with inorganic and/or organicacids and bases. Zwitterions (internal or inner salts) are includedwithin the term “salt(s)” as used herein (and may be formed, forexample, where the R substituents comprise an acid moiety such as acarboxyl group). Also included herein are quaternary ammonium salts suchas alkylammonium salts. Pharmaceutically acceptable (i.e., non-toxic,physiologically acceptable) salts are preferred, although other saltsare useful, for example, in isolation or purification steps which may beemployed during preparation. Salts of the compounds of the formula I maybe formed, for example, by reacting a compound I with an amount of acidor base, such as an equivalent amount, in a medium such as one in whichthe salt precipitates or in an aqueous medium followed bylyophilization.

Exemplary acid addition salts include acetates (such as those formedwith acetic acid or trihaloacetic acid, for example, trifluoroaceticacid), adipates, alginates, ascorbates, aspartates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates,hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates,lactates, maleates, methanesulfonates, 2-naphthalenesulfonates,nicotinates, nitrates, oxalates, pectinates, persulfates,3-phenylpropionatcs, phosphates, picrates, pivalates, propionates,salicylates, succinates, sulfates (such as those formed with sulfuricacid), sulfonates (such as those mentioned herein), tartrates,thiocyanates, toluenesulfonates, undecanoates, and the like.

Exemplary basic salts (formed, for example, where the R substituentscomprise an acidic moiety such as a carboxyl group) include ammoniumsalts, alkali metal salts such as sodium, lithium, and potassium salts,alkaline earth metal salts such as calcium and magnesium salts, saltswith organic bases (for example, organic amines) such as benzathines,dicyclohexylamines, hydrabamines, N-methyl-D-glucamines,N-methyl-D-glucamides, t-butyl amines, and salts with amino acids suchas arginine, lysine and the like. The basic nitrogen-containing groupsmay be quaternized with agents such as lower alkyl halides (e.g. methyl,ethyl, propyl, and butyl chlorides, bromides and iodides), dialkylsulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), longchain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides), aralkyl halides (e.g. benzyl and phenethylbromides), and others.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug”, as employed herein, denotes acompound which, upon administration to a subject, undergoes chemicalconversion by metabolic or chemical processes to yield a compound of theformula I, or a salt and/or solvate thereof. Solvates of the compoundsof formula I are preferably hydrates.

All stereoisomers of the present compounds, such as those which mayexist due to asymmetric carbons on the R substituents of the compound ofthe formula I, including enantiomeric and diastercomeric forms, arecontemplated within the scope of this invention. Individualstereoisomers of the compounds of the invention may, for example, besubstantially free of other isomers, or may be admixed, for example, asracemates or with all other, or other selected, stereoisomers. Thechiral centers of the present invention can have the S or Rconfiguration as defined by the IUPAC 1974 Recommendations.

Throughout the specification, groups and substituents thereof are chosento provide stable moieties and compounds.

Preferred compounds within the scope of the formula I include thosewherein:

-   Q₂ is phenyl optionally substituted with one or more groups as    defined in R_(1a) (especially, alkyl, hydroxy, alkoxy, haloalkoxy,    halo, nitro, —C(O)_(q)R₆, —C(O)_(q)H, -Z₄-NR₇R₈, -Z₄-N(R₁₂)-Z₅-Z₆,    or -Z₄-N(R₉)-Z₅-NR₁₀R₁₁);-   Z is selected from —S—, —CR₄R₅—S—, S—CR₄R₅—,    —CR₄R₅—O—CR_(4a)R_(5a)—, —CR₄R₅—NR⁴—CR_(4a)R_(5a)—, —CR₄R₅—,    —CR₄R₅-SO₂— or —CR₄R₅—S(O)—;-   R₁ is hydrogen;-   R₂ is hydrogen or alkyl; and-   R₃ is H, -Z₄R_(6a) or -Z₄NR_(7a)R_(8a).

More preferred compounds within the scope of formula I include thosewherein:

-   Q₂ is phenyl optionally substituted with one or more groups selected    from alkyl, alkoxy, hydroxy, —C(O)R₆ (especially wherein R₆ is    optionally substituted alkyl or heterocyclo (especially    piperazinyl), —C(O)NR₇R₈ or —NR₇R₈;-   Z is selected from —CR₄R₅—O—CR_(4a)R_(5a)—, —S—, —CR₄R₅—S— or    —S—CR₄R₅—;-   R₁ is hydrogen;-   R₂ is hydrogen or alkyl; and-   R₃ is Z₄R_(6a), especially where:    -   (a) Z₄ is a single bond and R_(6a) is optionally substituted        heteroaryl (preferably pyridinyl, pyrimidinyl, or quinolinyl        optionally substituted with one or more Z₁, Z₂ or Z₃ which are        preferably alkyl, hydroxyalkyl, halo, -Z₄-NZ₇Z₈, —C(O)_(q)H,        —C(O)_(q)Z₆, —OZ₆ or heterocyclo)    -   (b) Z₄ is —C(O)— and R_(6a) is        -   (1) aryl (especially phenyl) optionally substituted with one            or more Z₁, Z₂ or Z₃ (preferably -Z₄-NZ₇Z₈, —OZ_(a),            hydroxy, heterocyclo, or alkyl which may be optionally            substituted with any of the preceding preferred Z₁, Z₂ or Z₃            groups) (where present, at least one substituent is            preferably in the para position);        -   (2) alkyl optionally substituted with one or more Z₁, Z₂ or            Z₃;        -   (3) cycloalkyl (especially cyclopropyl) optionally            substituted with one or more Z₁, Z₂ or Z₃ (especially aryl,            aralkyl, halo, hydroxy, —C(O)_(q)H, —C(O)_(q)Z₆ or alkyl            optionally substituted with hydroxy, —OZ₆ or -Z₄-NZ₇Z₈)); or        -   (4) heterocyclo (especially pyrrolidinyl, piperidyl,            piperidenyl, piperazinyl, pyrrolyl, imidazolyl, pyrazolyl,            pyridinyl or pyrimidinyl) optionally substituted with one or            more Z₁, Z₂ or Z₃ (especially -Z₄-NZ₇Z₈, —C(O)_(q)H,            —C(O)_(q)Z₆, or alkyl optionally substituted with hydroxy,            —OZ₆ or -Z₄-NZ₇Z₈); or    -   (c) Z₄ is —C(O)—O— and R_(6a), is alkyl, cycloalkyl, aryl or        aralkyl, any of which may be optionally substituted with one or        more Z₁, Z₂ or Z₃.

Preferred compounds within the scope of formula I include compounds ofthe following formula II:

where Z, Q₂, R₁, R₂ and R₃ are as described above (including thedescription of preferred substituents). Additionally, preferredcompounds within the scope of formula II include compounds of thefollowing formulae IIIa, IIIb and IIIc:

where

-   Z is as described above (preferably —S—, —CR₄R₅—S—, or —S—CR₄R₅—    where R₄ and R₅ are H);-   R₁ is as described above (preferably H);-   R₂ and R₃ are as described above (including the description of    preferred substituents);-   R_(1aa) is —C(O)_(q)H, —C(O)_(q)R₆, -Z₄-NR₇R₈, -Z₄-N(R₉)-Z₅-NR₁₀R₁₁    or -Z₄-N(R₉)-Z₅-R₆; and-   R_(1ab), R_(1ac), and R_(1ad) are independently selected from any R₁    group (especially, H, alkyl, hydroxy, nitro, halo, —OR₆, —NR₇R₈,    —C(O)_(q)H or —C(O)_(q)R₆).

Preferred compounds within the scope of formulae III include compoundsof the following formula IV

where

-   Z, R₁, R_(1aa), R₂, and R₃ are as described above; and-   One of R_(1ab), R_(1ac) and R_(1ad) is H and the other two are    independently alkyl, alkoxy, haloalkoxy, hydroxy, nitro, halo,    —NR₇R₈, —C(O)_(q)H or —C(O)_(q)R₆) (preferably alkyl or alkoxy),    (preferably, R_(1c), is H when Z is —S—, and R_(1d) is H when Z is    —S—CR₄R₅— or —O—CR₄R₅—);

Compounds within the scope of formula IV include compounds of thefollowing formula V:

where

-   Z, R₁, R_(1ab), R_(1ac), R_(1ad), R₂ and R₃ are described for    formula IV;-   X₁ is C or N (preferably N);-   X₂ is CZ_(3a), NZ_(3a), O or S (preferably CZ_(3a), NZ_(3a) or O)    (more preferably NZ_(3a));-   Z₁ and Z₂ are as described for formula I (preferably H);-   Z_(3a) is H, hydroxy, optionally substituted alkyl (especially    optionally substituted with hydroxy, cyano, aryl, —OZ₆, Z₄-NZ₇Z₈,    —C(O)_(q)H or —C(O)_(q)Z₆), optionally substituted heterocyclo    (preferably optionally substituted piperidinyl, tetrazolyl,    pyridinyl, pyrimidinyl, or pyrrazolyl), optionally substituted aryl    or aralkyl (especially optionally substituted with halo), —OZ₆,    —C(O)_(q)H, —C(O)_(q)Z_(6a), -Z₄-NZ₇Z₈ (especially where Z₄ is a    bond or —(O)—), or -Z₄-N(Z₁₀)-Z₅-Z₆ (especially where Z₄ is a bond    or —C(O)— and Z₅ is —O—, —SO₂—, or —C(O)O—);-   n is 1 to 3; and-   m is zero to 2.

Methods of Preparation

The compounds of the formula I may be prepared by methods such as thoseillustrated in the following Schemes A through C and I through VIII.Solvents, temperatures, pressures, and other reaction conditions mayreadily be selected by one of ordinary skill in the art. All documentscited are incorporated herein by reference in their entirety. Startingmaterials are commercially available or readily prepared by one ofordinary skill in the art. Constituents of compounds are as definedelsewhere in the specification or as specifically defined in a scheme.

The methods described herein may be carried out with starting materialsand/or reagents in solution or alternatively, where appropriate, withone or more starting materials or reagents bound to a solid support (see(I) Thompson, L. A., Ellman, J. A., Chemical Reviews, 96, 555-600(1996); (2) Terrett, N. K., Gardner, M., Gordon, D. W., Kobylecki, R.J., Steele, J., Tetrahedron, 51, 8135-8173 (1995); (3) Gallop, M. A.,Barrett, R. W., Dower, W. J., Fodor, S. P. A., Gordon, E. M., Journal ofMedicinal Chemistry, 37, 1233-1251 (1994); (4) Gordon, E. M., Barrett,R. W., Dower, W. J., Fodor, S. P. A., Gallop, M. A., Journal ofMedicinal Chemistry, 37, 1385-1401 (1994); (5) Balkenhohl, F., von demBussche-Hünnefeld, Lansky, A., Zechel, C., Angewandte ChemieInternational Edition in English, 35, 2288-2337 (1996); (6) Balkenhohl,F., von dem Bussche-Hünnefeld, lansky, A., Zechel, C., AngewandteChemie, 108, 2436-2487 (1996); and (7) Sofia, M. J., Drugs DiscoveryToday, 1, 27-34 (1996)).

Compounds of formula I that contain chiral centers maybe obtained innon-racemic form by non-racemic synthesis or resolution by methods wellknown to those skilled in the art. Compounds that are non-racemic aredesignated as “chiral” in the examples.

In the examples described below it may be necessary to protect reactivefunctionality such as hydroxy, amino, thio or carboxy groups, wherethese are desired in the final product, to avoid their unwantedparticipation in reactions. The introduction and removal of protectinggroups are well known to those skilled in the art, for example see(Green, T. W. in “Protective Groups in Organic Synthesis”, John Wileyand Sons, 1991).

Scheme A illustrates a general method for forming compound Ia which is acompound of formula I where Z=O, S, or NR₄. Compound Ia can be formed byreacting compound i with compound ii in the presence of an organic orinorganic base e.g. alkalimetal alkoxide, alkyl or aryl lithium, orGrignard reagent in a protic or aprotic solvent e.g. tetrahydrofuran,ether, methyl alcohol, ethanol or dimethyl formamide at a temperature of78° C. to 100° C.

Scheme B illustrates a general method for forming compound Ia which is acompound of formula I where Z=O, S, NR₄. Compound Ia can be formed byreacting compound iii with compound iv in presence of an organic orinorganic base e.g. alkali metal alkoxide, alkalimetal hydride, alkyl oraryl lithium or Grignard reagent in a protic or a protic solvent e.g.THF, ether, methanol, ethanol or DMF at a temperature of −78° C. to 100°C.

Scheme C illustrates a general method for forming Compound Ib which is acompound of formula I where Z=CR₄R₅. Compound Ib can be formed byreacting Compound v with an organometallic reagent e.g. alkyl or aryllithium or cuprate or Grignard reagent and then reacting with Compoundvi in an aprotic solvent e.g. ether, THF, DMF at a temperature of −78°C. to 60° C.

Methods for preparing preferred examples of compound I are illustratedin Schemes I to IX.

As shown in Scheme I, amine Ic which can be formed by methods describedin Schemes A, B or C can be reacted with a chloroformate 1 ordicarbonate 2 to form Id. Compound Id can be treated with a base such assodium hydride, sodiun/potassium hexamethyl disilazide, or lithiumdiisopropylamide (LDA), and an alkylating agent R₂X where X is halogenand R₂ is preferably alkyl, arylalkyl or cycloalkylalkyl to formCompound Ie.

Scheme II illustrates methods which may be used for the preparation ofCompounds Ig, Ih, Ii, Ij and Ik which are compounds of formula I whereR₂ is any group as defined, R₃ is an acyl or thioacyl, Z is not —NH andR₁ is not a primary or secondary amine. Ig, Ih, Ii, Ij and Ik have otherparticular substituents which are specified in this Scheme and below.The starting compound If can be prepared by suitable methods describedin Schemes A, B or C.

Amide Ig can be prepared by treatment of amine If with a carboxylic acid3 in the presence of reagents which activate the carboxyl group forreaction as described above, for example BOP reagent, HATU andcarbodiimides such as DCC or EDCI either alone or in combination with ahydroxybenzotriazole. Alternatively, the alidhalide 4 may be reactedwith amine compound If in presence of an acid scavenger such as pyridineordiisopropyl ethyl amine. The corresponding thioamide Ih can beprepared by treatment of amide Ig with Lawesson's reagent as describedabove. Carbamate Ii can be prepared by treatment of amine compound Ifwith a chloroformate 1 or dicarbonate 2 in the presence of an acidscavenger such as diisopropylethylamine, triethylamine or an aqueousinorganic base such as sodium/potassium bicarbonate, sodium/potassiumcarbonate or hydroxide.

The urea Ij may be prepared by treatment of amine compound If witheither: 1) a chloroformate 1, such as phenyl chloroformate, followed byreaction with an amine 5; 2) a carbamoyl chloride 6 in presence of anacid scavenger such as diisopropylethylamine; or 3) reaction with anisocyanate 7a (where R_(c) in Ii=H). The corresponding thiourea Ik maybe prepared by treatment of amine compound Ie with a isothiocyanate 7b.Ra is selected from those groups included in the definition of R_(6a)such that the group —C(═A)—R_(a) is an acyl group within the definitionof R₃. Rb and Rc are selected from those groups included in thedefinitions of R_(7a) and R_(8a), such that the group —C(═A)-N(Rb)(Rc)is an acyl or thioacyl group within the definition of R₃.

Scheme III illustrates a method which can be used for the preparation ofII, which is a compound of formula I where R₂ is any group as definedother than acyl, and which is selected such that the nitrogen to whichit is attached is basic, R3 is alkyl, cycloalkyl, cycloalkyl-alkyl,cycloalkenylalkyl, aralkyl or saturated heterocycle and Z is not—NH. Thestarting compounds Ik and Ic can be prepared by suitable methodsdescribed in Schemes A, B and C. As shown in Scheme III, amine compoundIk is reacted with an aldehyde or ketone 8 under reductive aminationconditions described above to give the Compound II. Compound II may alsobe prepared by treatment of an amine compound Ic, where R₂ and R₃ arehydrogen, with t-butyl/t-amyl nitrite or sodium nitrite and an acid suchas HCl, H₂SO₄ in presence of a copper (II) halide to give the halocompound vii, followed by displacement with amine 9 in the presence orabsence of a base such as sodium or potassium hydride or the like (seeLee et al., J. Heterocyclic Chemistry 22, 1621, 1985). Rd and Re areindependently selected from hydrogen, alkyl, aryl, cycloalkyl orcycloalkenyl or together are alkylene or alkenylene completing a 3- to8-membered saturated or unsaturated ring, such that the group—CH(Rd)(Re) is a group within the definition of R.

As shown in Scheme IV, when R₂ is any group as defined other than acyl,and is selected such that the nitrogen to which it is attached is basic,R₃ is an aryl or heteroaryl, amine compound Ik may be reacted with ahalophenyl or haloheteroaromatic group 10 in the presence of aPd(0)catalyst (See J. Am. Chem. Soc. 118, 7215, 1996) to give amine II,which is a compound of formula I having the particular substituentsdescribed in this Scheme. The starting compound II can be prepared bysuitable methods described in Scheme A, B or C.

As shown in Scheme V, when R₂ is any group as defined, R₃ is aheteroaromatic group, amine compound, Im may be reacted, in the presenceof a base if needed, with a 2-halo-substituted heteroaromatic compound11 where Q_(a), together with atoms to which it is bonded, forms a 5- or6-membered monocyclic or 10- to 12-membered bicyclic heteroaromaticgroup (such as forming 2-chloropyridine, 2-chloropyrimidine or2-chloroquinoline) to give the amine compound In, where In is a compoundof formula I having the particular substituents described in thisscheme. The starting compound Im can be prepared by suitable methodsdescribed in Schemes A, B and C.

As shown in Scheme VI, thiourea compound Io may be reacted with theappropriate amine 12 in the presence of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP chloride), benzotriazol-1-yloxy-tris(dimethylamino) phosphonium hexafluorophosphate (BOP-reagent),[O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium]hexafluorophosphate(HATU) and a carbodiimide such as dicyclohexylcarbodiimide (DCC) or3-ethyl-e(dimethylamino) propyl carbodiimide (EDCI) ordiisopropylcarbodiimide (DIC) in the presence of an organic base such astriethylamine, diisopropylethylamine or dimethylaminopyridine insolvents such as dimethylformamide, dichloromethane or tetrahydrofuranto form compound Ip, which is a compound of formula I having theparticular substituents described in this scheme.

Alternatively, compound Io can be reacted with the appropriate amine 12in the presence of a mercury (II) salt such as mercury chloride, or byother known methods in the literature, to form Ip. The starting materialIo can be prepared by suitable methods described in Schemes A, B, or Cor Scheme II.

As shown in Scheme VII, amine Iq can be reacted with diphenylcyanocarbonimidate 13 either alone or in the presence of a base such assodium hydride, sodium/potassium hexamethyldisilazide ordimethylaminopyridine in acetonitrile, tetrahydrofuran ordimethylformamide at room temperature or elevated temperature to formintermediate compound Ir which can be reacted with amine 14 to formcompound Is which is a compound of formula I having the particularsubstituents described in this scheme. The starting material Iq can beprepared by suitable methods described in Schemes A, B or C.

As shown in Scheme VIII, compound Iq can be reacted with either 15 or 16either alone or in the presence of a base such as sodium hydride,sodium/potassium hexamethyldisilazide or dimethylaminopyridine indimethylformamide or tetrahydrofuran at room temperature or elevatedtemperature to form compounds It or Iu, respectively, which can bereacted separately with amine 14 at room temperature or elevatedtemperature to form compound Iv or Iw, respectively. Compounds Iv and Iware compounds of formula I having the particular substituents asdescribed in this scheme. The starting material Iq can be prepared bysuitable methods described in Schemes A, B or C.

As shown in Scheme IX, compound Ix may be reduced using, for example,lithium aluminum hydride in tetrahydrofuran at a temperature of 0-55°C., or reacted with alkyl or aryl metal derivatives, such as alkyllithium or Grignard reagents, in aprotic solvents such as diethyl etheror tetrahydrofuran, at a temperature of −78 to 100° C. to afford alcoholIy. Alcohol Iy may then be reacted with compound vi alone or in thepresence of organic or inorganic bases, such as sodium hydride, lithiumhexamethyldisilazide, or potassium t-butoxide and the like, in a solventsuch as dimethylformamide, and at a temperature of 0-100° C. to givecompound Iaa. Alternatively, the alcohol moiety of Iy may be transformedinto a leaving group via tosylation or conversion to a halide and thenreacted with compound 18 alone or in the presence of bases such assodium hydride in solvents such as tetrahydrofuran or dimethylformamideat a temperature from 0-100° C. to give compound Ibb.

Utility

The compounds of the present invention are immunosuppressive,anti-inflammatory, anti-allergic, and anti-cancer agents. The compoundsof the present invention inhibit Tec family tyrosine kinases (especiallyEmt) and are thus useful in the treatment, including prevention andtherapy, of Tec family tyrosine kinase-associated disorders, especiallyEmt-associated disorders. “Tec family tyrosine kinase-associateddisorders” are those disorders which result from aberrant Tec familytyrosine kinase activity, and/or which are alleviated by the inhibitionof one or more of these enzymes. Compounds within the scope of thepresent invention selectively inhibit Emt and are thus useful in thetreatment, including prevention and therapy, of a range of disordersassociated with the activation of Emt (e.g., inflammatory disorders,allergic disorders and cancer). In addition to Emt, the compounds of thepresent invention inhibit other Tee family kinases including Btk, Txk,Tec, and Bmx and are useful in the treatment of the disorders associatedwith the activation of these Tec family kinases. Such disorders areexemplified by, but are not limited to, transplant rejection;transplantation tolerance induction; arthritis including rheumatoidarthritis, psoriatic arthritis, and osteoarthritis; multiple sclerosis;chronic obstructive pulmonary disease (COPD) such as emphysema;inflammatory bowel diseases including ulcerative colitis and Crohn'sdisease; lupus (systemic lupus erythematosis); graft vs. host disease;T-cell mediated hypersensitivity diseases including contacthypersensitivity, delayed-type hypersensitivity, and gluten-sensitiveenteropathy (Celiac disease); psoriasis; contact dermatitis (includingthat due to poison ivy); Hashimoto's thyroiditis; Sjogren's syndrom;autoimmune hyperthyroidism such as Graves's disease; Addison's disease(autoimmune disease of the adrenal glands); autoimmune polyglandulardisease (also known as autoimmune polyglandular syndrome); autoimmunealopecia; pernicious anemia; vitiligo; autoimmune hypopituatarism;Guillain-Barre syndrome; diabetes (both type I and type II); otherautoimmune diseases; cancers such as leukemias and lymphomas;glomerulonephritis; serum sickness; uticaria; allergic diseasesincluding respiratory allergies (asthma, hayfever, allergic rhinitis)and skin allergies; scleracierma; mycosis fungoides; acute inflammatoryresponses (such as acute respiratory distress syndrome andischemia/reperfusion injury); dermatomyositis; alopecia areata; chronicactinic dermatitis; eczema; Behcet's disease; Pustulosis palmoplanteris;Pyoderma gangrenum; Sezary's syndrom; atopic dermatitis; systemicschlerosis; and morphea.

In a particular embodiment, the compounds of the present invention areuseful for the treatment of the aforementioned exemplary disordersirrespective of their etiology, for example, for the treatment oftransplant rejection, rheumatoid arthritis, multiple sclerosis, chronicobstructive pulmonary disease, inflammatory bowel disease, lupus, graftvs. host disease, T-cell mediated hypersensitivity disease, psoriasis,Hashimoto's thyroiditis, Guillain-Barre syndrom, cancer, contactdermatitis, allergic disease such as allergic rhinitis, asthma, ischemicor reperfusion injury, or atopic dermatitis whether or not associatedwith the Tec family tyrosine kinases.

The present invention also provides pharmaceutical compositionscomprising at least one of the compounds of the formula I capable oftreating a protein tyrosine kinase-associated disorder in an amounteffective therefor, and a pharmaceutically acceptable vehicle ordiluent. The compositions of the present invention may contain othertherapeutic agents as described below, and may be formulated, forexample, by employing conventional solid or liquid vehicles or diluents,as well as pharmaceutical additives of a type appropriate to the mode ofdesired administration (for example, excipients, binders, preservatives,stabilizers, flavors, etc.) according to techniques such as those wellknown in the art of pharmaceutical formulation.

The compounds of the formula I may be administered by any suitablemeans, for example, orally, such as in the form of tablets, capsules,granules or powders; sublingually; buccally; parenterally, such as bysubcutaneous, intravenous, intramuscular, or intrastemal injection orinfusion techniques (e.g., as sterile injectable aqueous or non-aqueoussolutions or suspensions); nasally such as by inhalation spray;topically, such as in the form of a cream or ointment; or rectally suchas in the form of suppositories; in dosage unit formulations containingnon-toxic, pharmaceutically acceptable vehicles or diluents. The presentcompounds may, for example, be administered in a form suitable forimmediate release or extended release. Immediate release or extendedrelease may be achieved by the use of suitable pharmaceuticalcompositions comprising the present compounds, or, particularly in thecase of extended release, by the use of devices such as subcutaneousimplants or osmotic pumps. The present compounds may also beadministered liposomally.

Exemplary compositions for oral administration include suspensions whichmay contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which may contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other cxcipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The present compounds may also be delivered through the oralcavity by sublingual and/or buccal administration. Molded tablets,compressed tablets or freeze-dried tablets are exemplary forms which maybe used. Exemplary compositions include those formulating the presentcompound(s) with fast dissolving diluents such as mannitol, lactose,sucrose and/or cyclodextrins. Also included in such formulations may behigh molecular weight excipients such as celluloses (avice)) orpolyethylene glycols (PEG). Such formulations may also include anexcipient to aid mucosal adhesion such as hydroxy propyl cellulose(HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methylcellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agentsto control release such as polyacrylic copolymer (e.g., Carbopol 934).Lubricants, glidants, flavors, coloring agents and stabilizers may alsobe added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions in saline which may contain, for example, benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, and/or other solubilizing or dispersing agents such asthose known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which may contain, for example, suitablenon-toxic, parenterally acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodiumchloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid.

Exemplary compositions for rectal administration include suppositorieswhich may contain, for example, a suitable non-irritating excipient,such as cocoa butter, synthetic glyceride esters or polyethyleneglycols, which are solid at ordinary temperatures, but liquify and/ordissolve in the rectal cavity to release the drug.

Exemplary compositions for topical administration include a topicalcarrier such as Plastibase (mineral oil gelled with polyethyleneglycol).

The effective amount of a compound of the present invention may bedetermined by one of ordinary skill in the art, and includes exemplarydosage amounts for an adult human of from about 0.1 to 100 mg/kg of bodyweight of active compound per day, which may be administered in a singledose or in the form of individual divided doses, such as from 1 to 4times per day. It will be understood that the specific dose level andfrequency of dosage for any particular subject may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the species, age, body weight, general health, sex and diet ofthe subject, the mode and time of administration, rate of excretion,drug combination, and severity of the particular condition. Preferredsubjects for treatment include animals, most preferably mammalianspecies such as humans, and domestic animals such as dogs, cats and thelike, subject to protein tyrosine kinase-associated disorders.

The compounds of the present invention may be employed alone or incombination with each other and/or other suitable therapeutic agentsuseful in the treatment of Tec family tyrosine kinase-associateddisorders such as Emt inhibitors other than those of the presentinvention, antiinflammatories, antiproliferatives, chemotherapeuticagents, immunosuppressants, anticancer agents and cytotoxic agents.

Exemplary such other therapeutic agents include the following: proteintyrosine kinase inhibitors (such as those disclosed in WO 00/62778),cyclosporins (e.g., cyclosporin A), CTLA4-g, LEA-29Y, antibodies such asanti-ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2,anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, monoclonal antibodyOKT3, agents blocking the interaction between CD40 and gp39, such asantibodies specific for CD40 and/or gp39 (i.e., CD154), fusion proteinsconstructed from CD40 and gp39 (CD4OIg and CD8gp39), inhibitors, such asnuclear translocation inhibitors, of NF-kappa B function, such asdeoxyspergualin (DSG), non-steroidal antiinflamatory drugs (NSAIDs) suchas ibuprofen, steroids such as prednisone or dexamethasone, goldcompounds, antiproliferative agents such as methotrexate, FK506(tacrolimus, Prograf), mycophenolate mofetil, cytotoxic drugs such asazathiprine and cyclophosphamide, phosphodiesterase (PDE) inhibitors,antihistamines, p³⁸ MAPK inhibitors, LTD₄ inhibitors such as zafirlukast(ACCOLATE) and montelukast (SINGULAIR), TNF-α inhibitors such astenidap, anti-TNF antibodies or soluble TNF receptor such as etanercept(Enbrel), rapamycin (sirolimus or Rapamune), leflunimide (Arava), andcyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Celebrex) androfecoxib (Vioxx), or derivatives thereof, and the PTK inhibitorsdisclosed in the following U.S. patent applications, incorporated hereinby reference in their entirety: Ser. No. 60/056,770, filed Aug. 25,1997, Ser. No. 60/069,159, filed Dec. 9, 1997, Ser. No. 09/097,338,filed Jun. 15, 1998, Ser. No. 60/056,797, filed Aug. 25, 1997, Ser. No.09/094,797, filed Jun. 15, 1998, Ser. No. 60/065,042, filed Nov. 10,1997, Ser. No. 09/173,413, filed Oct. 15, 1998, Ser. No. 60,076,789,filed Mar. 4, 1998, and Ser. No. 09,262,525, filed Mar. 4, 1999. See thefollowing documents and references cited therein: Hollenbaugh, D.,Douthwright, J., McDonald, V., and Aruffo, A., “Cleavable CD40Ig fusionproteins and the binding to sgp39”, J. Immunol. Methods (Netherlands),188(1), p. 1-7 (Dec. 15 1995); Hollenbaugh, D., Grosmaire, L. S.,Kullas, C. D., Chalupny, N. J., Braesch-Andersen, S., Noelle, R. J.,Stamenkovic, I., Ledbetter, J. A., and Aruffo, A., “The human T cellantigen gp39, a member of the TNF gene family, is a ligand for the CD40receptor: expression of a soluble form of gp39 with B cellco-stimulatory activity”, EMBO J (England), 11(12), p 4313-4321(December 1992); and Moreland, L. W. et al., “Treatment of rheumatoidarthritis with a recombinant human tumor necrosis factor receptor(p75)-Fc fusion protein, New England J. of Medicine, 337(3), p. 141-147(1997).

Exemplary classes of anti-cancer agents and cytotoxic agents include,but are not limited to: alkylating agents, such as nitrogen mustards,alkyl sulfonates, nitrosoureas, ethylenimines, and triazenes;antimetabolites, such as folate antagonists, purine analogues, andpyrimidine analogues; antibiotics, such as anthracyclines, bleomycins,mitomycin, dactinomycin, and plicamycin; enzymes, such asL-asparaginase; farnesyl-protein transferase inhibitors; hormonalagents, such as glucocorticoids, estrogens/antiestrogens,androgens/antiandrogens, progestins, and luteinizing hormone-releasingbormone anatagonists, octreotide acetate; microtubule-disruptor agents,such as ecteinascidins or their analogs and derivatives;microtubule-stabilizing agents such as paclitaxel (Taxol®), docetaxel(Taxotere®), and epothilones A-F or their analogs or derivatives;plant-derived products, such as vinca alkaloids, epipodophyllotoxins,taxanes-; and topoisomerase inhibitors; prenyl-protein transferaseinhibitors; and miscellaneous agents such as, hydroxyurea, procarbazine,mitotane, hexamethylmelamine, platinum coordination complexes such ascisplatin and carboplatin; and other agents used as anti-cancer andcytotoxic agents such as biological response modifiers, growth factors;immune modulators, and monoclonal antibodies. The compounds of theinvention may also be used in conjunction with radiation therapy.

Representative examples of these classes of anti-cancer and cytotoxicagents include, but are not limited to, mechlorethamine hydrochloride,cyclophosphamide, chlorambucil, melphalan, ifosfamide, busulfan,cannustin, lomustine, semustine, streptozocin, thiotepa, dacarbazine,methotrexate, thioguanine, mercaptopurine, fludarabine, pentastatin,cladribin, cytarabine, fluorouracil, doxorubicin hydrochloride,daunorubicin, idarubicin, bleomycin sulfate, mitomycin C, actinomycin D,safracins, saframycins, quinocarcins, discodermolides, vincristine,vinblastine, vinorelbine tartrate, etoposide, teniposide, paclitaxel,tamoxifen, estramustine, estramustine phosphate sodium, flutamide,buserelin, leuprolide, pteridines, diyneses, levamisole, aflacon,interferon, interleukins, aldesleukin, filgrastim, sargramostim,rituximab, BCG, tretinoin, irinotecan hydrochloride, betamethosone,gemcitabine hydrochloride, altretamine, and topoteca and any analogs orderivatives thereof.

Preferred members of these classes include, but are not limited topaclitaxel, cisplatin, carboplatin, doxorubicin, carminomycin,daunorubicin, aminopterin, methotrexate, methopterin, mitomycin C,ecteinascidin 743, porfiromycin, 5-fluorouracil, 6-mercaptopurine,gemcitabine, cytosine arabinoside, podophyllotoxin or podophyllotoxinderivatives such as etoposide, etoposide phosphate or teniposide,melphalan, vinblastine, vincristine, leurosidine, vindesine, andleurosine.

Examples of anti-cancer and other cytotoxic agents include thefollowing: epothilone derivatives as found in U.S. Ser. No. 09/506,481filed Feb. 17, 2000 German Patent No. 4138042.8; WO 97/19086, WO98/22461, WO 98125929, WO 98/38192, WO 99/01124, WO 99/02224, WO99/02514, WO 99/03848, WO 99/07692, WO 99/27890, WO 99/28324, WO99/43653, WO 99/54330, WO 99/54318, WO 99/54319, WO 99/65913, WO99/67252, WO 99/67253, and WO 00/00485; cyclin dependent kinaseinhibitors as found in WO 99/24416; and prenyl-protein transferaseinhibitors as found in WO 97/30992 and WO 98/54966.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art.

Compounds within the scope of the present invention can be assayed forTec family tyrosine kinase inhibitory activity using methods such asthose described by Hawkins, J. and Marcy, A. Prof. Express. Purif. 2001,22, 211-219, employing modifications readily known to those of skill inthe art.

The following example compounds are Tec family tyrosine kinaseinhibitors (especially Emt inhibitors) and illustrate embodiments of thepresent invention. These examples are not intended to limit the scope ofthe claims. Compounds of the Examples are identified by the example andstep in which they are prepared (for example, “1A” denotes the titlecompound of step A of Example 1), or by the example only where thecompound is the title compound of the example (for example, “2” denotesthe title compound of Example 2).

EXAMPLE 1N-[5-[[3[-(4-Acetylpiperazin-1-yl)carbonyl]phenyl]thio]thiazol-2-yl]-4-(N,N-dimethylamino)benzamide

A. [3-((2-Aminothiazol-5-yl)thio]benzoic acid methyl ester

A 4.37 M solution of sodium methoxide in methanol (10 mL, 43.7 mmol) wasadded dropwise to a stirred suspension of 2-amino-5-bromothiazolehydrochloride (2.16 g, 10 mmol) and 3-carboxythiophenol (1.85 g, 12mmol) in methanol (75 mL) at 0-5° C. The solution was allowed to warm tort. for 2 h and a 4 M solution of hydrogen chloride in dioxane (15 mL,60 mmol) was added. The suspension was stirred at rt. overnight andconcentrated. The crude residue was diluted with satd. aqueous sodiumbicarbonate solution (50 mL). The precipitated solid was filtered andwashed with water (20 mL, 5×) and ether (20 mL, 5×). The solid wasfiltered and dried in vacuo at 60° C. to obtain the titled compound(1.97 g, 75%).B. 3-[[2-[[((1,1-Dimethylethoxy)carbonyl]amino]thiazol-5-yl]thio]benzoicacid methyl ester

Di-t-butylcarbonate (4.36 g, 20 mmol) was added to a stirred solution of2-amino-5-[(3-carbomethoxyphenyl)thio]thiazole (1.33 g, 5 mmol) and4-N,N-dimethylaminopyridine (62 mg, 0.5 mmol) in THF (120 mL). Thesolution was stirred at rt. for 6 h and concentrated. The residue waspurified using flash column chromatography on silica gel. Elution with10% EtOAc in hexanes followed by 25% EtOAc in hexanes afforded a mixtureof the titled compound and the correspondingbis(tert-butoxycarbonyl)amino adduct (1.8 g) as an oil.C. 3-[[2-[[(1,1-Dimethylethoxy)carbonyl]amino]thiazol-5-yl]thio]benzoicacid

A 1 N aqueous sodium hydroxide solution (50 mL, 50 mmol) was addeddropwise to a stirred solution of2-tert-butoxycarbonylamino-5-[(3-carbomethoxyphenyl)thio]thiazole (1.8g, (contaminated with bis(tert-butoxycarbonyl)amino adduct)) in amethanol-THF mixture (160 mL, 3:1). The solution was stirred at rt. for24 h and concentrated. The residue was acidified with 2 N aqueous HCl(30 mL) and the suspension was extracted with dichloromethane-methanolmixture (120 mL, 3:1, 2×). The combined organic extract was dried(MgSO₄), filtered and concentrated in vacuo to obtain the titledcompound (1.32 g, 75% overall yield from Example 1, part A) as anoff-white solid.D.5-[[3-[(4-Acetylpiperazin-1-yl)carbonyl]phenyl]thio]thiazol-2-ylcarbamicacid 1,1-(dimethylethyl) ester

A suspension of2-tert-butoxycarbonylamino-5-[(3-carboxyphenyl)thio]thiazole (528 mg,1.5 mmol), N-acetylpiperazine (239 mg, 1.87 mmol),ethyl-3-(3-dimethylamino)propyl carbodiimide hydrochloride (400 mg, 2mmol), 1-hydroxy-7-azabenzotriazole (272 mg, 2 mmol) anddiisopropylethylamine (560 μL, 4 mmol) in THF (20 mL) was heated to 55°C. for 2 h. The mixture was cooled to rt. and concentrated. The residuewas purified using column chromatography on silica gel eluted with 2%methanol in dichloromethane followed by 5% methanol in dichloromethaneto obtain the titled compound (400 mg, 58%) as a white foam.E. 4-Acetyl-1-[3-[(2-aminothiazol-5-yl)thio]benzoyl]piperazine

A solution of2-tert-butoxycarbonylamino-5-[(3-N-acetylpiperazinylcarboxamidopbenyl)thio]thiazole(400 mg, 0.87 mmol) in trifluoroacetic acid (6 mL) was stirred at rt.for 2 h. The solution was concentrated and the residue was partitionedbetween dichloromethane (30 mL) and satd. aqueous sodium bicarbonatesolution (20 mL). The aq. layer was extracted with dichloromethane (20mL). The dichloromethane extracts were combined, dried (IMgSO₄),filtered and concentrated under reduced pressure and in vacuo to obtainthe titled compound (300 mg, 95%) as a white solid.F.N-[5-[[3-[(4-Acetylpiperazin-1-yl)carbonyl]phenyl]thio]thiazol-2-yl]-4-(N,N-dimethylamino)benzamide

A stirred suspension of2-amino-5-[(3-N-acetylpiperazinylcarboxamido-phenyl)-thio]thiazole (30mg, 0.08 mmol), and 4-N,N-dimethylaminobenzoyl chloride (45.6 mg, 0.25mmol) in dichloromethane (6 mL) was cooled to 0° C. and treated withpyridine (130 mL). The cooling bath was removed and the solution wasstirred at rt. for 2 h. The mixture was concentrated in vacuo and theresidue was purified using reversed phase automated preparative HPLC(conditions: YMC S5 ODS A 20×100 mm column, 15 min gradient startingfrom 10% solvent B (90% MeOH, 10% H₂O, 0.1% TFA) and 90% solvent A (10%MeOH, 90% H₂O, 0.1% TFA) to 90% solvent B and 10% solvent A, flow rate20 mL/min, λ=220 nM to obtain the titled compound (8.7 mg, 21%) as ayellow solid: (M+H)⁺=510.27.

EXAMPLE 24-Acetyl-1-[5-[[2-[N-(6-bromopyridin-2-yl)amino]thiazol-5-yl]thio]-2-methylbenzoyl]piperazine

A. N-[[N-(6-Bromopyridin-2-yl)amino]thioxo]benzamide

A solution of 2-amino-6-bromopyridine (3 g, 17.34 mmol) and benzoylisothiocyanate (2.3 mL, 17.34 mmol) in acetone (30 mL) was stirred atrt. for 35 min. The suspension was cooled in an ice-water bath, dilutedwith water (150 mL) and stirred for several min. The precipitate wasfiltered, washed with water and dried in vacuo. The solid was trituratedwith ether to obtain the titled compound (4.99 g, 86%) as an off-whitesolid.B. N-(6-Bromopyridin-2-yl)thiourea

A suspension of 2-bromo-6-benzoylthioureidopyridine (4.99 g, 14.84 mmol)in 10% aqueous sodium hydroxide solution (10.4 mL, 26 mmol) was stirredat rt. for 10 min and then under reflux for an additional 10 min. Themixture was cooled to 0° C. and acidified with 1 N aqueous HCl solutionto pH 4.0 and then adjusted to pH 8.5 with satd. aqueous potassiumbicarbonate solution. The mixture was stirred at 0° C. for several minand the precipitate was filtered, washed several times with water anddried in vacuo over P₂O₅ to obtain the titled compound (3.23 g, 94%) asa white solid.C. 6-Bromo-N-(2-thiazolyl)pyridin-2-amine

A suspension of 2-bromo-6-thioureidopyridine (3 g, 12.92 mmol) andchloroacetaldehyde (3.28 mL, 25.85 mmol) in ethanol (27 mL) and water (7mL) was heated at reflux for 4.75 h. The solution was concentrated invacuo and the residue was diluted with 1 N aqueous NaOH solution at 0°C., stirred for 10 min, and the pH was then adjusted to 8.5 by additionof 6 N aqueous HCl solution. The precipitate was collected byfiltration, washed several times with water and dried in vacuo over P₂O₅to obtain the titled compound (3.17 g, 96%) as a light yellow solid.D. 6-Bromo-N-(5-bromo-2-thiazolyl)pyridin-2-amine

A solution of bromine (1.1 mL, 20.9 mmol) in acetic acid (15 mL) wasadded dropwise to a solution of 2-[(6-bromo-2-pyridinyl)amino]thiazole(2.68 g, 10.46 mmol) in acetic acid (23 mL) at 40° C. After addition,the mixture was stirred at rt. for 3 h. The mixture was diluted withaqueous potassium hydrogen sulfate solution (60 mL) at 0° C. and stirredfor several min. The precipitated solid was filtered, washed severaltimes with water and dried in vacuo over P₂O₅ to obtain the titledcompound (3.28 g, 94%) as an off-white solid.E.5-[[2-[N-(6-Bromopyridin-2-yl)amino]thiazol-5-yl]thio]-2-methylbenzoicacid

A suspension of 2-[(6-bromo-2-pyridinyl)amino]-5-bromothiazole (100 mg,0.3 mmol), 3-carboxy-4-methylthiophenol (170 mg, 0.98 mmol) and sodiummethoxide (210 μL, 25% w/w solution in methanol, 0.9 mmol) in methanol(4.9 mL) and THF (2 mL) was heated to 54° C. for 5.5 h. Supplementalsodium methoxide solution (1.42 mL) was added in portions over a periodof 5 h. The mixture was heated to 54° C. for 16 h and concentrated. Theresidue was diluted with 1 N aqueous HCl solution at 0° C. and stirredfor several minutes. The precipitated solid was filtered, washed severaltimes with water and ether, and dried in vacuo over P₂O₅. Triturationwith ether afforded the titled compound (103 mg, 81%) as an off-whitesolid.F.4-Acetyl-1-[5-[[2-[N-(6-bromopyridin-2-yl)amino]thiazol-5-yl]thio]-2-methylbenzoyl]piperazine

A suspension of2-[(6-bromo-2-pyridinyl)amino]-5-(3-carboxy-4-methylphenyl-1-thio)thiazole(103 mg, 0.24 mmol), N-acetylpiperazine (37.2 mg, 0.29 mmol),ethyl-3-(3-dimethylamino)propyl carbodiimide hydrochloride (55.6 mg,0.29 mmol), 1-hydroxy-7-azabenzotriazole (39.5 mg, 0.29 mmol) anddiisopropylethylamine (130 mL, 0.72 mmol) in THF (10.5 mL) was heated to58° C. for 1 h. The mixture was concentrated in vacuo and the residuewas purified using column chromatography on silica gel. Elution with 1%methanol in dichloromethane followed by 2% and 4% methanol indichloromethane afforded the titled compound (110 mg, 86%) as a yellowsolid: mass spectrum (M+H)⁺=533.89.

EXAMPLE 34-Acetyl-1-[5-[[2-[N-(2-pyridinyl)amino]thiazol-5-yl]thio]-2-methylbenzoyl]piperazine

A. N-[[N-(2-Pyridinyl)amino]thioxo]benzamide

This material was prepared by an analogous method as that of Example 2,part A, except using 2-aminopyridine to give the title compound as anochre solid (100%).B. N-(2-Pyridinyl)thiourea

This material was prepared by an analogous method as that described inExample 2, part B, except using the compound described in Example 3,part A to give the title compound as a yellow powder (73%).C. N-(2-Thiazolyl)-2-pyridinamine

Example 3C was prepared by an analogous method as that of Example 2C,except using the compound described in Example 3, part B to give thetitle compound as an off-white solid (79%).D. N-(5-Bromothiazol-2-yl)-2-pyridinamine

Example 3D was prepared by an analogous method as that of Example 2D,except using the compound described in Example 3, part C to give thetitle compound as an off-white solid (95%).E. 2-Methyl-5-[[2-[N-(2-pyridinyl)amino]thiazol-5-yl]thio]benzoic acid

Example 3E was prepared by an analogous method as that of Example 2E,except using the compound described in Example 3, part D to give thetitle compound as a pale tan solid (84%).F.4-Acetyl-1-[5-[[2-[N-(2-pyridinyl)amino]thiazol-5-yl]thio]-2-methylbenzoyl]piperazine

Example 3F was prepared by an analogous method as that of Example 2F,except using the compound described in Example 3, part E to give thetitle compound as an off-white solid: mass spectrum (M+H)⁺=454.11.

EXAMPLE 44-Acetyl-1-[3-[[2-[N-(6-bromopyridin-2-yl)amino]thiazol-5-yl]thio]benzoyl]piperazine

A. 3-[[2-[N-(6-Bromopyridin-2-yl)amino]thiazol-5-yl]thio]benzoic acid

Example 4A was prepared by an analogous method as that of Example 2E,except using 3-carboxythiophenol in place of3-carboxy-4-methylthiophenol to give the title compound as a solid.B.4-Acetyl-1-[3-[[2-[N-(6-bromopyridin-2-yl)amino]thiazol-5-yl]thio]benzoyl]piperazine

Example 4B was prepared by an analogous method as that of Example 2F,except using the compound described in Example 4, part A to give thetitle compound as a light peach-colored solid: mass spectrum(M+H)⁺=520.13.

EXAMPLE 54-Acetyl-1-[3-[[2-[N-(2-pyridinyl)amino]thiazol-5-yl]thio]benzoyl]piperazine

A. 3-[[2-[N-(2-Pyridinyl)amino]thiazol-5-yl]thio]benzoic acid

Example 5A was prepared by an analogous method as that of Example 2E,except using the compound described in Example 3, pan D and3-carboxythiophenol in place of 3-carboxy-4-methylthiophenol to give thetitle compound as a solid.B.4-Acetyl-1-[3-[[2-[N-(2-pyridinyl)amino]thiazol-5-yl]thio]benzo-yl]piperazine

Example 5B was prepared by an analogous method as that of Example 2F,except using the compound described in Example 5, part A to give thetitle compound as an off-white solid: mass spectrum (M+H)⁺=440.3.

EXAMPLE 64-Acetyl-1-[3-[[2-[N-(6-methylpyridin-2-yl)amino]thiazol-5-yl]thio]benzoyl]piperazine

Example 6 was prepared by an analogous method as that of Example 2,except using 2-amino-6-methylpyridine in place of2-amino-6-bromopyridine in Example 2A and 3-carboxythiophenol in placeof 3carboxy-4-methylthiopbenol in Example 2E to give the title compoundas a white solid: mass spectrum (M+H)⁺=454.11.

EXAMPLE 74-Acetyl-1-[3-[[2-[N-(5-bromo-6-methylpyridin-2-yl)amino]thiazol-5-yl]thio]benzoyl]piperazine

Example 7 was prepared by an analogous method as that of Example 2,except using 2-amino-5-bromo-6-methylpyridine in place of2-amino-6-bromopyridine in Example 2A and 3-carboxythiophenol in placeof 3-carboxy-4-methylthiophenol in Example 2E to give the title compoundas a light tan solid: mass spectrum (M+H)⁺=534.

EXAMPLE 84-Acetyl-1-[3-[[2-[N-(2-quinolinyl)amino]thiazol-5-yl]thio]benzoyl]piperazine

Example 8 was prepared by an analogous method as that of Example 2,except using 2-amino-quinoline in place of 2-amino-6-bromopyridine inExample 2A and 3-carboxythiophenol in place of3-carboxy-4-methylthiophenol in Example 2E to give the title compound asa yellow solid: mass spectrum (M+H)⁺=490.08.

EXAMPLE 94-Acetyl-1-[3-[[2-[N-(2-pyridinyl)amino]thiazol-5-yl]thio]-4-methylbenzoyl]piperazine

Example 9 was prepared by an analogous method as that of Example 2,except using 2-amino-pyridine in place of 2-amino-6-bromopyridine inExample 2A and 3-carboxy-6-methylthiophenol in place of3-carboxy-4-methylthiophenol in Example 2E to give the title compound asa white solid: mass spectrum (M+H)⁺=454.13.

EXAMPLE 104-Acetyl-1-[3-[[2-[N-[6-(1-piperidinyl)pyridin-2-yl]amino]thiazol-5-yl]thio]benzoyl]piperazine

A solution of Example 4 (30 mg, 0.058 mmol), piperidine (86 μL, 0.87mmol), 4-dimethylaminopyridine (7.1 mg, 0.058 mmol) in pyridine (300 μL)was heated to 134° C. in a sealed vial under nitrogen for 8.75 h. Mostof pyridine was removed on a speed-vac at 40° C. The residue waspurified using reversed phase automated preparative HPLC (conditions:YMC S5 ODS A 20×100 mm column, 15 min gradient starting from 10% solventB (90% MeOH, 10% H₂O, 0.1% TFA) and 90% solvent A (10% MeOH, 90% H₂O,0.1% TFA ) to 90% solvent B and 10% solvent A, flow rate 20 mL/min,λ=220 nM) to obtain the titled compound (25.2 mg, 68%) as a light tansolid.

EXAMPLES 11 THROUGH 22

General Procedure

Polymer-supported diisopropylethylamine (37.6 mg, 0.124 mmol) wasdispensed into each well of a 48 well Mini-block reactor. A 0.087 Msolution of the appropriate amines in THF-DMF mixture (1 mL, 9:1) wasadded to each well using the TECAN liquid handler. A solution of thecarboxylic acid described in procedure 3E (10 mg, 0.029 mmol),ethyl-3-(3-dimethylamino)propylcarbodiimide hydrochloride (6.71 mg,0.035 mmol), 1-hydroxy-7-azabenzotriazole (4.76 mg, 0.035 mmol) inTHF-DMF mixture (1 mL, 4:1) was added to each well using the TECANliquid handler. The Mini-block was sealed and mechanically shaken at 60°C. for 5 h and at room temperature for an additional 16 h. Polystyrenesupported methylisocyanate resin (109.5 mg, Novabiochem) was added toeach well and shaking was continued at room temperature for 16 h. Eachreaction mixture was loaded onto cation-exchange cartridges (CUBCX1HL,size: 500 mg/3 mL, United Chemical Technologies) and eluted sequentiallywith THF (8 mL), MeOH (8 mL), and 0.2 N ammonia in MeOH (4 mL).Fractions containing products were concentrated using a speed-vac.Residues were dissolved in THF-DMF mixture (9:1) and passed throughanion exchange cartridges (CHQAX1, size: 500 mg/3 mL, United ChemicalTechnologies) and eluted with MeOH (2 mL). Fractions containing theproducts were concentrated using the speed-vac to give Examples 11-22.

Ex. MS No. Name Structure (M + H)⁺ 11 4-(2-Pyrimidinyl)-1-[5-[[2- [N-(2-pyridinyl)amino]thiazol- 5-yl]thio]-2- methylbenzoyl]piperazine

488.3 12 4-Hydroxy-1-[5-[[2-[N-(2- pyridinyl)amino]thiazol-5-yl]thio]-2- methylbenzoyl]piperidine

427.33 13 1,2,5,6-Tetrahydro-1-[5- [[2-[N-(2- pyridinyl)amino]thiazol-5-yl]thio]-2- methylbenzoyl]pyridine

409.2 14 4-[2-(4-Morpholinyl)-2- oxoethyl]-1-[5-[[2-[N-(2-pyridinyl)amino]thiazol]- 5-yl]thio]-2- methylbenzoyl]piperazine

456.2 15 3-(Hydroxymethyl)-1-[5- [[2-[N-(2- pyridinyl)amino]thiazol-5-yl]thio]-2- methylbenzoyl]piperidine

441.15 16 4-(1-Piperidinyl)-1-[5-[[2- [N-(2- pyridinyl)amino]thiazol-5-yl]thio]-2- methylbenzoyl]piperidine

494.3 17 4-Formyl-1-[5-[[2-[N-(2- pyridinyl)amino]thiazol- 5-yl]thio]-2-methylbenzoyl]piperazine

440.08 18 3-Methyl-1-[5-[[2-[N-(2- pyridinyl)amino]thiazol-5-yl]thio]-2- methylbenzoyl]piperidine

425.18 19 N-Methyl-N-phenyl-4-[5- [[2-[N-(2- pyridinyl)amino]thiazol-5-yl]thio]-2- methylbenzoyl]-1- piperazineacetamide

559.3 20 4-[5-[[2-[N-(2- Pyridinyl)amino]thiazol- 5-yl]thio]-2-methylbenzoyl]-1- piperazineacetic acid ethyl ester

498.18 21 N-(2-Cyanoethyl)-2- methyl-5-[[2-[N-(2-pyridinyl)amino]thiazol- 5-yl]thio]benzamide

396.14 22 N-(Cyanomethyl)-2- methyl-5-[[2-[N-(2-pyridinyl)amino]thiazol- 5-yl]thio]benzamide

382.12

EXAMPLE 23N-[15-[[5-[(4-Acetylpiperazin-1-yl)carbonyl]-2-methylphenyl]thio]thiazol-2-yl]-4-(N,N-dimethylamino)benzamide

A. 3-[(2-Aminothiazol-5-yl)thio]-4-methylbenzoic acid methyl ester

A 4.37 M solution of sodium methoxide in methanol (4.75 mL, 20.76 mmol)was added dropwise to a stirred suspension of 2-amino-5-bromothiazolehydrobromide (1.25 g, 4.8 mmol) and 3-carboxy-6-methyl-thiophenol (0.74g, 4.4 mmol) in methanol (75 mL) at 0-5° C. The solution was stirred at75° C. overnight. The mixture was concentrated in vacuo and the residuewas dissolved in water and then acidified with aqueous HCl solution. Theprecipitated brown solid was filtered, washed with water and dried invacuo to obtain the carboxylic acid (1.15 g). A solution of this acid inMeOH, 4 N hydrogen chloride in dioxane and conc. H₂SO₄ (20 drops) washeated under reflux for 3 days. The solution was concentrated and theresidue was partitioned between EtOAc and satd. aqueous NaHCO₃ solution.The EtOAc extract was washed with satd. aqueous NaHCO₃ solution, dried(Na₂SO₄), filtered and concentrated in vacuo to obtain the titlecompound (1 g, 81%) as a yellowish-brown solid.B.3-[[2-[[4-(N,N-Dimethylamino)benzoyl]amino]thiazol-5-yl]thio]-4-methylbenzoicacid methyl ester

A suspension of compound A (1 g, 3.6 mmol), and4-N,N-dimethylaminobenzoyl chloride (1.31 g, 7.1 mmol) indichloromethane (25 mL) and pyridine (1 mL) was stirred at rt. for 2days. Supplemental 4-N,N-dimethylaminobenzoyl chloride (500 mg, 2.72mmol) was added and the mixture was stirred at rt. overnight. Thesolution was partitioned between dichloromethane and water. Thedichloromethane extract was washed with 1 N aq. HCl solution, satd. aq.NaHCO₃ solution, dried (Na₂SO₄), filtered, and concentrated in vacuo toobtain the crude product, which was used without further purification.C.3-[[2-[[4-(N,N-Dimethylamino)benzoyl]amino]thiazol-5-yl]thio]-4-methylbenzoicacid

A 1 N aqueous sodium hydroxide solution (25 mL, 25 mmol) was addeddropwise to a stirred solution of crude compound B in methanol. Thesolution was stirred at rt. for 72 h and concentrated. The residue waspartitioned between dichloromethane and water. The aqueous extract wasacidified with 1 N aqueous HCl solution and the precipitated solid wascollected by filtration and dried in vacuo to obtain the title compoundC (850 mg, 58%) as a tan solid.D.N-[5-[[5-[(4-Acetylpiperazin-1-yl)carbonyl]-2-methylphenyl]thio]thiazol-2-yl]-4-(N,N-dimethylamino)benzamide

A suspension of compound C (380 mg, 0.92 mmol), N-acetylpiperazine (236mg, 1.84 mmol), ethyl-3-(3-dimethylamino)propyl carbodiimidehydrochloride (350 mg, 1.8 mmol), 1-hydroxy-7-azabenzotriazole (250 mg,1.8 mmol) and diisopropylethylamine (1 mL, 7.1 mmol) in THF (20 mL) washeated to 66° C. overnight. The mixture was cooled to rt. andconcentrated. The residue was purified using reversed phase automatedpreparative HPLC (conditions: YMC S5 ODS A 20×100 mm column, 15 mingradient starting from 10% solvent B (90% MeOH, 10% H₂O, 0.1% TFA) and90% solvent A (10% MeOH, 90% H₂O, 0.1% TFA ) to 90% solvent B and 10%solvent A, flow rate 20 mL/min, λ=220 nM) to obtain the title compound(73 mg, 15% yield) as a yellow solid: mass spectrum (M+H)⁺=524.14.

EXAMPLE 24N-[5-[[3-[(4-Acetylpiperazin-1-yl)carbonyl]-4-methylphenyl]thio]thiazol-2-yl]-4-(N,N-dimethylamino)benzamide

Compound 24 was prepared by an analogous method as that of 23, exceptsubstituting 3-carboxy-4-methylthiophenol in place of3-carboxy-6-methylthiophenol in Example 23A to give the title compound24 as an orange solid: mass spectrum (M+H)⁺=524.11.

EXAMPLE 25N-[5-[[3-[(4-Acetylpiperazin-1-yl)carbonyl]-4,5-dimethylphenyl]thio]thiazol-2-yl]-4-(N,N-dimethylamino)benzamide

Example 25 was prepared by an analogous method as that of Example 23,except substituting 3-carboxy-4,5-dimethylthiophenol for3-carboxy-6-methylthiophenol in Example 23A to give the title compoundas a light salmon colored solid: mass spectrum (M+H)⁺=538.33.

EXAMPLE 26N-[5-[[3-[(4-Acetylpiperazin-1-yl)carbonyl]-4-aminophenyl]thio]thiazol-2-yl]-4-(N,N-dimethylamino)benzamide

Example 26 was prepared by an analogous method as that of 23, exceptsubstituting 3-carboxy-4-acetamido-thiophenol for3-carboxy-6-methylthiophenol in Example 23A to give the title compoundas a yellow solid: mass spectrum (M+H)⁺=525.21.

EXAMPLE 27N-[5-[[5-[(4-Acetylpiperazin-1-yl)carbonyl]-2,4-dimethylphenyl]thio]thiazol-2-yl]-4-(N,N-dimethylamino)benzamide

Example 27 was prepared by an analogous method as that of 23, exceptsubstituting 3-carboxy-4,6-dimethylthiophenol for3-carboxy-6-methylthiophenol in Example 23A to give the title compoundas a light amber solid: mass spectrum (M+H)⁺=538.44.

EXAMPLE 28N-[5-[[3-[(4-Acetylpiperazin-1-yl)carbonyl]-4-hydroxyphenyl]thio]thiazol-2-yl]-4-(N,N-dimethylamino)benzamide

Example 28 was prepared by an analogous method as that of 23, exceptsubstituting 3-carboxy-4-hydroxy-thiophenol for3-carboxy-6-methylthiophenol in Example 23A to give the title compoundas a yellow solid: mass spectrum (M+H)⁺=526.45.

EXAMPLE 29N-[5-[[5-[(4-Acetylpiperazin-1-yl)carbonyl]-2,4-dimethylpheny]thio]thiazol-2-yl]-4-(1,1-dimethylethyl)benzamide

Example 29 was prepared by an analogous method as that of 23, exceptsubstituting 3-carboxy-4,6-dimethylthiophenol for3-carboxy-6-methylthiophenol in Example 23A and substituting4-tert-butylbenzoyl chloride for 4-N,N-dimethylaminobenzoyl chloride inExample 23B to give the title compound as an amber solid: mass spectrum(M+H)⁺=551.12.

EXAMPLE 304-(1,1-Dimethylethyl)N-[5-[[5-[(4-hydroxypiperidin-1-yl)carbonyl]-2,4-dimethylphenyl]thio]thiazol-2-yl]benzamide

Example 30 was prepared by an analogous method as that of 23, exceptsubstituting 3-carboxy-4,6-dimethylthiophenol for3-carboxy-6-methylthiophenol in Example 23A, substituting4-t-butylbenzoyl chloride for 4-N,N-dimethylaminobenzoyl chloride inExample 23B and substituting 4-hydroxypiperidine for N-acetylpiperazincin Example 23D to give the title compound as an amber solid: massspectrum (M+H)⁺=524.32.

EXAMPLE 31N-[5-[[[3-[(4-Acetylpiperazin-1-yl)carbonyl]phenyl]methoxy]methyl]thiazol-2-yl]-4-(1,1-diimethylethyl)benzamide

A. 2-[N-[4-(1,1-Dimethylethyl)benzoyl]amino]thiazole-5-carboxylic acidethyl ester

A solution of ethyl 2-aminothiazole-5-carboxylate (0.52 g, 3.0 mmol),4-t-butylbenzoyl chloride (1.3 mL, 6.7 mmol) and pyridine (1.2 mL) indichloromethane (10 mL) was stirred at 0° C. for 1.25 h. It was thendiluted with dichloromethane and washed with aqueous HCl (1 N) twice,saturated aqueous sodium bicarbonate, and brine. After drying oversodium sulfate, filtration and concentration in vacuo gave a burgundyoil. Trituration with hexane afforded the desired amide as a light tansolid (0.88 g, 88% yield): LC/MS RT=3.85 min; mass spectrum(M+H)⁺=333.16.B. 4-(1,1-Dimethylethyl)-N-[(5-hydroxymethyl)thiazol-2-yl]benzamide

To a light tan suspension of ethyl2-[[4-(1,1-dimethylethyl)phenyl)carbonyl]amino)-thiazole-5-carboxylate(0.88 g, 2.6 mmol) in tetrahydrofuran (7.0 mL) under nitrogen at 0° C.was added dropwise lithium aluminum hydride (1 M in THF, 10.6 mL). After1.75 h, ice was added, followed by 1 N aqueous HCl. The mixture wasextracted using ethyl acetate, and the combined organic layers weredried over sodium sulfate, filtered, and concentrated in vacuo to givethe desired product as a light yellow solid (0.73 g, 95% yield): LC/MSRT =3.11 min; mass spectrum (M+H)⁺=291.13.C. 4-Acetyl-1-(3-chloromethyl)benzoylpiperazine

To a solution of 3-chloromethylbenzoyl chloride (5.34 g, 28.2 mmol) indichloromethane (25 mL) was added a solution of 1-acetylpiperazine (7.30g, 57.0 mmol) in dichloromethane (25 mL) at 0° C. over 10 min. Theresulting mixture was stirred at 0° C. for 1 hour and then at roomtemperature for another hour. During the reaction period, the mixturebecame cloudy. It was diluted with dichloromethane, washed with water, 1N HCl, water, brine, and dried over anhydrous MgSO₄. Evaporation ofsolvent gave the desired product (7.92 g, 100%) as a pale yellow viscousoil: LC/MS RT=0.92 min; mass spectrum (M+H)⁺=281.19.D.N-[5-[[[3-[(4-Acetylpiperazin-1-yl)carbonyl]phenyl]methoxy]methyl]thia-zol-2-yl]-4-(1,1-dimethylethyl)benzamide

To a solution of2-[[4-(1,1-dimethylethyl)phenyl)carbonyl]amino]-5-hydroxymethylthiazole(0.285 g, 0.983 mmol) and N-acetylpiperazinyl-(3-chloromethyl)benzamide(0.276 g, 0.983 mmol) in DMF (30 mL) at 0° C. was added NaH (60%dispersion in mineral oil, 0.197 g, 4.92 mmol). The mixture was heatedat 60° C. overnight and was quenched by adding MeOH. The solution wasneutralized to pH 8 using 1 N HCl and diluted with ethyl acetate Thesolution was then washed with water, brine, dried over anhydrous MgSO₄,and concentrated under vacuum. The residue was purified using flashcolumn chromatography (5% MeOH/CHCl₃) to afford 30 mg of the desiredmaterial as a white solid: LC/MS RT=3.49 min; mass spectrum(M+H)⁺=535.20.

EXAMPLE 324-(1,1-Dimethylethyl)-N-[5-[[[3-[[(4-(2-pyrimidinyl)piperazin-1-yl]carbonyl]-4-methylphenyl]thio]methyl]thiazol-2-yl]benzamide

A. N-[(5-Chloromethyl)thiazol-2-yl]-4-(1,1-dimethylethyl)benzamide

To a solution of2-[[4-(1,1-dimethylethyl)phenyl)carbonyl]amino]-5-hydroxymethylthiazole(1.50 g, 5.16 mmol) in dichloromethane (40 mL) was added thionylchloride (1.50 mL, 20.6 mmol) at 0° C. The mixture was stirred for 2 h,after which the reaction was complete, as indicated by HPLC. Evaporationof solvent and excess thionyl chloride provided the desired material(1.58 g, 99%) as a pale yellow solid.B.5-[[[2-[[4-(1,1-Dimethylethyl)benzoyl]amino]thiazol-5-yl]methyl]thio]-2-methylbenzoicacid

To a solution of 3-mercapto-2-methylbenzoic acid (0.270 g, 1.60 mmol) inDMF (5 mL) was added KOBu^(t) (0.378 g, 3.20 mmol) at 0° C. The mixturewas stirred at 0° C. for 20 min before5-chloromethyl-2-[[4-(1,1-dimethylethyl)phenyl)carbonyl]-amino]thiazole(0.445 g, 1.44 mmol) was added. The mixture was stirred at 0° C. for 1 hand then poured into water (20 mL). The solution was acidified to pH 2using 1 N HCl. The precipitate was collected by filtration and driedover drierite under vacuum. The product (0.489 g, 77%) was obtained as awhite solid: LC/MS RT=3.96 min; mass spectrum (M+H)⁺=441.14.C.4-(1,1-Dimethylethyl)-N-[5-[[[3-[[4-(2-pyrimidinyl)piperazin-1-yl]carbonyl]-4-methylphenyl]thio]methyl]thiazol-2-yl]benzamide

A mixture of the product of Example 32, part B (0.250 g, 0.567 mmol),1-(2-pyrimidyl)piperazine (0.121 g, 0.737 mmol),benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate(0.476 g, 1.08 mmol), 4-methylmorpholine (0.31 mL, 2.82 mmol) in DMF (6mL) was heated at 65° C. for 5 h. The mixture was then diluted withethyl acetate, washed with water, 1N NaOH solution, water, and brine.The solution was dried over anhydrous MgSO₄ and concentrated undervacuum. The residue was purified using flash column chromatography(ethyl acetate) to provide the desired product (0.210 g, 63%) as a whitesolid: LC/MS RT=3.94 min; mass spectrum (M+H)⁺=587.42.

EXAMPLE 33N-[5-[[N-[3-[(4-Acetylpiperazin-1-yl)carbonyl]phenylmethyl]-N-methylamino]methyl]thiazol-2-yl]-4-(1,1-dimethylethyl)benzamide

A. 4-Acetyl-1-[3-[(N-methylamino)methyl]benzoyl]piperazine

To N-Acetylpiperazinyl-(3-chloromethyl)benzamide (32C, 0.884 g, 3.15mmol) was added methylamine (2.0 M in MeOH, 4.7 mL). The mixture wasstirred at room temperature overnight. It was then diluted with water(20 mL), adjusted to pH 11 using 10% NaCO₃ solution, and extracted withethyl acetate (5×30 mL). The combined organic extract was dried overanhydrous MgSO₄ and concentrated under vacuum. The residue was purifiedusing flash column chromatography (30% MeOH/CHCl₃-80% MeOH/CHCl₃) toafford the desired amine (0. 142 g, 16%) as a pale yellow viscous oil;LC/MS RT=1.42 min, mass spectrum (M+H)⁺=276.23.B.N-[5-[[N-[3-[(4-Acetylpiperazin-1-yl)carbonyl]phenylmethyl]-N-methylamino]methyl]thiazol-2-yl]-4-(1,1-dimethylethyl)benzamide

To a solution of 33A (72.0 mg, 0.261 mmol) in THF (3 mL) was added5-chloromethyl-2-[[4-(1,1-dimethylethyl)phenylcarbonyl]amino]thiazole(32A, 80.0 mg, 0.259 mmol) in one portion at 0° C. The mixture wasstirred room temperature for 3 h and then at 45° C. for 2 h. It was thendiluted with water (20 mL), adjusted to pH 11 using 10% NaCO₃ solution,and extracted with ethyl acetate (5×30 mL). The combined extract wasdried over anhydrous MgSO₄ and concentrated in vacuo. The residue waspurified using preparative HPLC to afford 13.3 mg of the desiredmaterial as a TFA salt; LC/MS RT=2.60 min, mass spectrum (M+H)⁺=548.28.

EXAMPLE 34N-15-[[3-[(4-Acetylpiperazin-1-yl)carbonyl]-4-methyl-6-methoxy-phenyl]thio]thiazol-2-yl]-4-(N-1,2-dimethylpropylaminomethyl)benzamide

A. [3-[(2-Aminothiazol-5-yl)thio]-4-methyl-6-methoxy]benzoic acid

A 4.37 M solution of sodium methoxide in methanol (33.7 mL, 147.3 mmol)was added dropwise to a stirred suspension of 2-amino-5-bromothiazolehydrobromide (9.96 g, 38.3 mmol) and3-carboxy-4-methoxy-6-methyl-thiophenol (5.84 g, 27.5 mmol) in methanol(95 mL) at 0-5° C. under argon. The cooing bath was removed and thesolution was stirred at rt. for 1 hr. The mixture was cooled to 0° C.and acidified with a 4 M solution of hydrogen chloride in dioxane (37mL, 148 mmol). Supplemental hydrogen chloride in dioxane was addedslowly to adjust the pH to 2. Precipitated salts were filtered andwashed with methanol. The filtrate was concentrated under reducedpressure and the residual solid was washed with water (2×15 mL). Thesolid was dried in vacuo, and triturated with ether to obtain the titledcompound (8.52 g, 87%) as a tan solid.B.5-[[[3-[(4-Acetylpiperazin-1-yl)carbonyl]-4-methyl-6-methoxy]phenyl]thio]-2-amino-thiazole

A suspension of[3-[(2-aminothiazol-5-yl)thio]-4-methyl-6-methoxy]benzoic acid (2 g, 6mmol), N-acetylpiperazine (3.1 g, 24 mmol),ethyl-3-(3-dimethylamino)propyl carbodiimide hydrochloride (2.3 g, 12mmol), 1-hydroxy-7-azabenzotriazole (980 mg, 7.2 mmol) anddiisopropylethylamine (4.2 mL, 24 mmol) in THF (50 mL) and DMF (6 mL)was heated to 64° C. for 2.25 hr. The mixture was cooled to rt. andconcentrated in vacuo. The residue was dissolved in dichloromethane andwashed with water (50 mL) and 1 N aq. HCl solution (4×100 mL). Theaqeous layers were combined, brought to slightly alkaline pH using 1 Naq. NaOH solution and extracted with dichloromethane (6×70 mL). Thedichloromethane extracts were combined, dried (Na₂SO₄), filtered, andconcentrated. The residue was triturated with ether (90 mL) to obtainthe titled product (1.99 g, 82%) as a light tan solid.C.N-[5-[[[3-[(4-Acetylpiperazin-1-yl)carbonyl]-4-methoxy-6-methyl]phenyl]thio]thiazol-2-yl]-4-(chloromethyl)benzamide

A solution of5-[[[3-[(4-acetylpiperazin-1-yl)carbonyl]-4-methyl-6-methoxy]phenyl]thio]-2-aminothiazole(102 mg, 0.28 mmol), 4-chloromethyl-benzoyl chloride (53 mg, 0.28 mmol)and diisopropylethyl amine (140 μL, 1 mmol) in dichloromethane (8 mL)was stirred at rt. for 3 hr. Supplemental 4-chloromethylbenzoyl chloride(26 mg, 0.14 mmol) was added and the solution was stirred for anadditional 4 hr. The mixture was diluted with dichloromethane (40 mL)and washed with 1 N aq. HCl solution (2×10 mL) and aq. NaHCO₃ solution(2×15 mL). The dichloromethane extract was dried (MgSO₄), filtered, andconcentrated in vacuo to obtain the crude titled product (205 mg) as ayellow foam.D.N-[5-[[3-[(4-Acetylpiperazin-1-yl)carbonyl]-4-methyl-6-methoxy-phenyl]thio]thiazol-2-yl]-4-(N-1,2-dimethylpropylaminomethyl)benzamide

A solution of crudeN-[5-[[[3-[(4-acetylpiperazin-1-yl)carbonyl]-4-methoxy-6-methyl]phenyl]thio]thiazol-2-yl]-4-(chloromethyl)benzamide(205 mg, 0.25 mmol) and 1,2-dimethylpropyl amine (87 mg, 1 mmol) inmethanol (10 mL) was heated to 60° C. in a sealed tube for 24 hr. Themixture was cooled to rt. and concentrated in vacuo. The residue waspurified using reverse phase automated preparative HPLC (conditions: YMCS5 ODS 30×250 mm column, 30 min gradient starting from solvent A (10%MeOH, 90% H₂O, 0.1% TFA) to solvent B (90% MeOH, 10% H₂O, 0.1% TFA),flow rate 25 mL/min, λ=220 nM) to obtain the titled compound as a TFAsalt (100 mg, 55% yield over two steps, white foam); LC/MS RT=2.79 min;mass spectrum (M+H)⁺=610.32.

EXAMPLE 354-Acetyl-1-[5-[[2-[N-(6-bromopyridin-2-yl)amino]thiazol-5-yl]oxo]-2-methylbenzoyl]piperazine

A. 5-[[2-[N-(6-Bromopyridin-2-yl)amino]thiazol-5-yl]oxo]-2-methylbenzoicacid ethyl ester

A suspension of 2-[(6-bromo-2-pyridinyl)amino]-5-bromothiazole (Example2, part D: 400 mg, 1.19 mmol), ethyl 3-hydroxy-6-methylbenzoate (330 mg,1.79 mmol) and cesium carbonate (1.6 g, 4.76 mmol) in acetone (16 mL)was heated under reflux for 16 hr. The mixture was cooled to rt. andcesium carbonate was filtered through a Whatman Autovial PTFE filter.The filtrate was concentrated, diluted with dichloromethane andfiltered. The filtrate was concentrated and the residual brown oil waspurified using silica gel column chromatography. Elution with 5% EtOAcin hexanes followed by 10%, 20%, 30%, and 50% EtOAc in hexanes affordedthe title product (90 mg, 21%) as a light tan solid.B. 5-[[2-[N-(6-Bromopyridin-2-yl)amino]thiazol-5-yl]oxo]-2-methylbenzoicacid

A solution of5-[[2-[N-(6-bromopyridin-2-yl)amino]thiazol-5-yl]oxo]-2-methylbenzoicacid ethyl ester (90 mg, 0.21 mmol) and 1 N aq. NaOH solution (1.3 mL,1.3 mmol) in THF (2 mL) and ethanol (2 mL) was stirred at rt. for 24 hr.The mixture was cooled to 0° C. and acidified with 6 N aq. HCl solution.After eveporation of the solvents in vacuo, the residue was diluted withwater and the precipitate was filtered, washed with water, and dried invacuo to obtain the titled compound (57 mg, 67%) as a yellow solid.C.4-Acetyl-1-5-[[2-[N-(6-bromopyridin-2-yl)amino]thiazol-5-yl]oxo]-2-methylbenzoyl]piperazine

A suspension of5-[[2-[N-(6-bromopyridin-2-yl)amino]thiazol-5-yl]oxo]-2-methylbenzoicacid (27.9 mg, 0.07 mmol), N-acetylpiperazine (17.9 mg, 0.14 mmol),ethyl-3-(3-dimethylamino)propyl carbodiimide hydrochloride (26.8 mg,0.14 mmol), 1-hydroxy-7-azabenzotriazole (11.3 mg, 0.08 mmol) anddiisopropylethylamine (37 μL, 0.21 mmol) in THF (2.3 mL) and DMF (0.4mL) was heated to 60° C. for 3.25 hr. The mixture was cooled to rt. andconcentrated in vacuo on a speed vac. The residue was purified usingsilica gel column chromatography (5% acetone in dichloromethane followedby 1% and 2% methanol in dichloromethane) to afford the titled product(34 mg, 75%) as a light tan solid: LC/MS RT=1.90 min; mass spectrum(M+H)⁺=516.45.

EXAMPLE 364-Acetyl-1-[5-[[2-[N-(6-chloro-2-methyl-pyrimidin-4-yl)amino]thiazol-5-yl]thio]-2-methoxy-4-methylbenzoyl]piperazine

Sodium hydride (43.9 mg, 1.83 mmol) was added to a solution of5-[[[3-[(4-acetylpiperazin-1-yl)carbonyl]4-methyl-6-methoxy]phenyl]thio]-2-aminothiazole(Example 34, part B: 250 mg, 0.61 mmol) and2-methyl-4,6-dichloropyrimidine (200 mg, 1.23 mmol). The mixture washeated to 50° C. for 16 hr, cooled to rt, and supplemental sodiumhydride (43.9 mg, 1.83 mmol) was added. The mixture was heated to 50° C.for an additional 3 hr, cooled to rt, and excess hydride was quenched bythe addition of glacial acetic acid. The mixture was concentrated invacuo, diluted with satd. aq. NaHCO₃ solution, and extracted withTHF-EtOAc mixture (4×). The organic extracts were combined, washed withsatd. aq. NaHCO₃ solution, brine, dried (NaSO₄), filtered, andconcentrated in vacuo to obtain a tan solid which was triturated withether-EtOAc (4:1) to obtain the titled compound (260 mg, 80%) as a lighttan solid.

EXAMPLE 374-Acetyl-1-[5-[2-[N-(6-N,N-dimethylaminoethylamino-2-methyl-pyrimidin-4-yl)amino]thiazol-5-yl]thio]-2-methoxy-4-methylbenzoyl]piperazine

A solution of4-acetyl-1-[5-[[2-[N-(6-chloro-2-methyl-pyrimidin-4-yl)amino]thiazol-5-yl]thio]-2-methoxy-4-methylbenzoyl]piperazine(Example 36: 10 mg, 0.019 mmol), N,N-dimethylethylenediamine (10 mL,0.094 mmol), and 4-dimethylaminopyridine (2.32 mg, 0.019 mmol) indioxane (1 mL) was heated to 100° C. in a sealed vial for 16 hr. Themixture was purified using reversed phase automated preparative HPLC(conditions: YMC 20×100 mm column, 10 min gradient starting from 90%solvent A (10% McOH, 90% H₂O, 0.1% TFA) and 10% solvent B (90% MeOH, 10%H₂O, 0.1% TFA) and final solvent:90% solvent B and 10% solvent A, flowrate 20 mL/min, λ=220 nM) to obtain the titled compound as a TFA salt(14 mg, 36% yield, tan solid): LC/MS RT=1.34 min; mass spectrum(M+H)⁺=585.16.

EXAMPLE 38

A. 2-Amino-5-[(5-carbomethoxy-4-methoxy-2-methylphenyl)thio]thiazole

To a suspension of the compound described in Example 34, part A (2.00 g,6.75 mmol) in MeOH (100 mL) was added HCl in diethyl ether (2.0 M, 10mL) at rt. The mixture was heated at reflux overnight before MeOH wasremoved under vacuum. To the residue was added water (50 mL). Theresulting mixture was adjusted to pH 12 with 1 N NaOH solution and thenextracted with EtOAc (4×40 mL). The combined extract was washed withwater and brine, and dried over anhydrous MgSO₄. Evaporation of solventunder vacuum provided the titled compound (1.73 g, 82% yield) as a tansolid.B.2-[[(Cyclopropyl)carbonyl]amino]-5-[(5-carbomethoxy-4-methoxy-2-methylphenyl)thio]thiazole

A mixture of the compound from part A (1.73 g, 5.57 mmol),cyclopropylcarboxylic acid (95%, 0.69 mL, 8.28 mmol),1-[(3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.90 g,9.91 mmol), and 4-dimethylaminopyridine (0.070 g, 0.57 mmol) in CH₂Cl₂(120 mL) was heated at reflux overnight. The mixture was cooled to rt,diluted with CH₂Cl₂ (50 mL), and washed with water, 1 N HCl solution, 1N NaOH solution, water, and brine. The organic fraction was then driedover anhydrous MgSO₄. Evaporation of solvent under vacuum provided thetitled compound (1.91 g, 90% yield) as a beige solid.C.2-[[(Cyclopropyl)carbonyl]amino]-5-[(5-carboxy-4-methoxy-2-methylphenyl)thio]thiazole

A mixture of the compound from part B (0.550 g, 1.45 mmol) and I N NaOH(4.4 mL, 4.4 mmol) in THF (20 mL) was heated at reflux for 5 hr. Solventwas removed under vacuum, and the residue was acidified to pH 2 with 1 NHCl. The resulting precipitate was collected by suction filtration,washed with water, and dried over drierite under vacuum to afford thetitled compound (0.484 g, 92% yield) as a beige solid.D.2-[[(Cyclopropyl)carbonyl]amino]-5-[(4-methoxy-2-methyl-5-piperazinylcarboamidophenyl)thio]thiazole

A solution of the compound from part C (0.252 g, 0.690 mmol.),piperazine (0.300 g, 3.60 mmol),(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP, 0.622 g, 1.40 mmol) and N-methylmorpholine (0.38 mL, 3.5 mmol) inDMF (7.0 mL) was heated in an oil bath at 65° C. for 2 hr. After coolingto room temperature, the reaction mixture was diluted with EtOAc andwashed with water (2×). The organic layer was dried over sodium sulfate,filtered, and concentrated in vacuo to give the first crop of product(0.0805 g, 27% yield). The aqueous layers were combined and extractedwith dichloromethane (5×). The organic layers were combined, dried oversodium sulfate, filtered and concentrated in vacuo. Silica gelchromatography using dichloromethane:methanol:acetic acid (10:0.4:0.2)as eluent afforded the second crop of product (0.1860 g, 62% yield) as awhite solid: LC/MS (M+H)⁺=433.56.E.2-[[(Cyclopropyl)carbonyl]amino]-5-[[(4-methoxy-2-methyl-5-[[(4-tert-butoxycarbonylamino)aceto]piperazinylcarboxamido]phenyl]thio]thiazole

A mixture of the compound from part D (46.5 mg, 0.107 mmol),N-Boc-glycine (38.5 mg, 0.22 mmol), BOP (92.9 mg, 0.21 mmol), andN-methylmorpholine (0.060 mL, 0.55 mmol) in DMF (0.5 mL) wasmechanically shaken at 65° C. overnight. The reaction mixture wasdiluted with MeOH (0.5 mL), purified using preparative HPLC andlyophilized to give the titled compound (51.6 mg, 82% yield) as a whitepowder.

F. Title Compound

To a solution of the compound from part E (40.1 g, 0.068 mmol) indichloromethane (1.0 mL) under nitrogen at 0° C. was addedtrifluoroacetic acid (1.0 mL). After 3 hr, the reaction mixture wasconcentrated in vacuo and triturated with diethyl ether to give thedesired product (30.8 mg, 75% yield) as a white solid: LC/MS(M+H)⁺=490.2 1.

EXAMPLE 39

A mixture of2-[[(cyclopropyl)carbonyl]amino]-5-[(4-methoxy-2-methyl-5-piperazinylcarboamidophenyl)thio]thiazole(Example 38, part D: 46.5 mg, 0.107 mmol), N-methylglycine (19.6 mg,0.22 mmol), BOP (92.9 mg, 0.21 mmol), and N-methylmorpholine (0.060 mL,0.55 mmol) in DMF (0.5 mL) was mechanically shaken at 65° C. overnight.The reaction mixture was diluted with MeOH (0.5 mL), purified usingpreparative HPLC, and lyophilized to give the title compound as a whitepowder TFA salt (27.3 mg, 41% yield): LC/MS (M+H)⁺=504.14.

EXAMPLE 40

This material was prepared in the same manner as Example 39: LC/MS(M+H)⁺=518.22.

EXAMPLE 41

A mixture of2-[[(cyclopropyl)carbonyl]amino]-5-[(4-methoxy-2-methyl-5-piperazinylcarboamidophenyl)thio]thiazole(Example 38, part D: 20.0 mg, 0.0549 mmol), 1-(2-pyrimidyl)piperazine(18.0 mg, 0.110 mmol), BOP (36.4 mg, 0.0823 mmol), andN-methylmorpholine (0.027 mL, 0.246 mmol) in DMF (0.5 mL) was stirred at55° C. overnight. The reaction mixture was diluted with MeOH (0.5 mL)and purified using preparative HPLC. The appropriate fractions werecombined and concentrated, and the pH adjusted to 12 with 1 N NaOHfollowed by extraction with CH₂Cl₂ (3×20 mL). The combined extract wasdried over anhydrous MgSO₄. Evaporation of solvent under vacuum providedthe desired product (20 mg, 71% yield) as a white solid: LC/MS(M+H)⁺=511.17.

EXAMPLE 42

This material was prepared in the same manner as Example 41: LC/MS(M+H)⁺=511.15.

EXAMPLE 43

A.2-Amino-5-[(4-methoxy-2-methyl-5-[[(morpholinyl)carboxamido]phenyl]thio]thiazole

A mixture of2-Amino-5-[(5-carboxy-4-methoxy-2-methylphenyl)thio]thiazole (Example34, part A: 1.00 g, 3.37 mmol), morpholine (0.59 mL, 6.74 mmol), BOP(2.24 g, 5.06 mmol), and N-methylmorpholine (1.60 mL, 14.6 mmol) in DMF(10 mL) was heated at 60° C. for 2.5 hr. The solution was diluted withEtOAc (150 mL), then washed with water (3×40 mL) and brine (40 mL). Theaqueous layer was extracted with EtOAc (2×50 mL) and the combinedorganic layer was dried over anhydrous MgSO₄. The solution wasconcentrated under vacuum, and the residue purified using flashchromatography (silica gel, 6% MeOH/CHCl₃) to give the titled compound(0.935 g, 76% yield) as a tan solid.B.2-[[(5-Formyl-2-pyrrolyl)carbonyl]amino]-5-([[(morpholinyl)carboxamido]phenyl]thio]thiazole

To a suspension of 5-formyl-2-pyrrole carboxylic acid (0.320 g, 2.30mmol) in CH₂Cl₂ (25 mL) at ° C. was added thionyl chloride, and theresulting mixture heated at reflux for 1.5 hr. The solvent and excessthionyl chloride was evaporated under vacuum. Residual thionyl chloridewas removed by adding toluene (1 mL) and concentrating the mixture todryness under vacuum. The residue was dissolved in CH₂Cl₂ (25 mL), andto the resulting solution was added a solution of the compound of part A(0.927 g, 2.54 mmol) and pyridine (1.1 mL, 13.6 mmol) in CH₂Cl₂ (30 mL).The mixture was heated at reflux for 2.5 hr before it was concentratedto dryness under vacuum. To the solid residue was added 0.5 N HCl (40mL) and the mixture was well stirred for 10 min. The precipitate wascollected by suction filtration, washed with water, and dried overdrierite under vacuum to give the title compound (0.880 g, 71% yield) asa tan solid.C.2-[[(5-Hydroxymethyl-2-pyrrolyl)carbonyl]amino]-5-[[(morpholinyl)carboxamido]phenyl]thio]thiazole

To a suspension of the compound from part B (0.400 g, 0.822 mmol) in DMF(40 mL) and MeOH (20 mL) was added NaBH₄ (0.622 g, 16.4 mmol) at 0° C.in one portion. The mixture was stirred at rt. overnight, after whichperiod the heterogeneous mixture became a clear solution. The reactionwas quenched with water (5 mL), and the resulting solution wasconcentrated to approximately 20 mL. The residue was diluted with water(40 mL), extracted with EtOAc (3×40 mL) and CH₂Cl₂ (3×40 mL). Thecombined organic layer was concentrated under vacuum. To the residue wasadded Et₂O (20 mL). The resulting precipitate was collected byfiltration, washed with water, and dried over drierite under vacuum toprovide the title product (0.226 g, 56% yield) as a beige solid.D. Title Compound

A mixture of the compound from part C (80 mg, 0.164 mmol) and thionylchloride (2 mL) was heated at 60° C. for 1.5 hr. The excess thionylchloride was evaporated under vacuum. Residual thionyl chloride wasremoved by adding toluene (1 mL) and concentrating the mixture todryness under vacuum. The residue was dissolved in anhydrous DMF (2 mL),and to the resulting solution was added NH₃/MeOH (7 M solution, 7 mL, 7mmol). The mixture was heated in a sealed tube at 55° C. for 16 hr.After cooling to rt, the reaction mixture was poured into 1 N HClsolution (15 mL). The resulting mixture was extracted with EtOAc (3×20mL). The aqueous solution was adjusted to pH 12 with 10% NaOH solution,and extracted with EtOAc (4×30 mL). The combined extract was dried overanhydrous MgSO₄, and concentrated under vacuum. The residue was purifiedusing preparative HPLC and lyophilized to provide the titled product(3.0 mg, 3% yield) as a white powder, TFA salt: LC/MS (M+H)⁺=488.14.

EXAMPLE 44

To a mixture of the compound of Example 43, part B (40 mg, 0.082 mmol)and MeNH₂/THF (2.0 M solution, 0.16 mL, 0.32 mmol) in anhydrous DMF (8mL) at rt. was added NaBH(OAc)₃ (71 mg, 0.32 mmol) in one portion. Themixture was stirred at rt. for 6 hr before supplementary NaBH(OAc)₃ (35mg, 0.16 mmol) was added. The mixture was allowed to stir at rt.overnight before it was quenched with saturated NaHCO₃ solution (10 mL).The mixture was then diluted with EtOAc (100 mL) and washed with water(3×25 mL). The aqueous solution was extracted with EtOAc (50 mL). Thecombined organic phase was washed with 10% LiCl solution (35 mL), andconcentrated under vacuum. The residue was purified using preparativeHPLC and lyophilized to provide the title product (22.7 mg, 45% yield)as a white powder, TFA salt: LC/MS (M+H)⁺=502.17.

EXAMPLE 45

This material was prepared in a similar manner as Example 44: LC/MS(M+H)⁺=516.2.

EXAMPLE 46

This material was prepared in the same manner as Example 44: LC/MS(M+H)⁺=532.19.

EXAMPLE 47

To a mixture of the compound from Example 43, part B (20 mg, 0.041 mmol)and 1,2-dimethylpropylamine (7.2 mg, 0.082 mmol) in anhydrous DMF (4 mL)at rt. was added NaBH(OAc)₃ (17 mg, 0.082 mmol) in one portion. Themixture was stirred at rt. for 20 hr before supplementary NaBH(OAc) (26mg, 0.12 mmol) was added. The mixture was allowed to stir at rt. for anadditional 24 hr before it was quenched with saturated NaHCO3 solution(10 mL). The resulting mixture was diluted with EtOAc, washed with water(2×) and brine, and concentrated under vacuum. The residue was dissolvedin MeOH (5 mL), and to the resulting solution was added 1 N HCl (2 mL).The mixture was then heated at reflux for 1.5 hr. After cooling to rt,the solution was adjusted to pH 12 with 1N NaOH solution, diluted withwater (5 mL), and extracted with EtOAc (3×). The combined extract waswashed with brine and concentrated under vacuum. The residue waspurified using preparative HPLC and lyophilized to provide the desiredproduct (4.6 mg, 17% yield) as a white powder, TFA salt: LC/MS(M+H)⁺=558.34.

EXAMPLE 48

This material was prepared in the same manner as Example 44: LC/MS(M+H)⁺=530.37.

EXAMPLE 49

A mixture of 2-pyrrolecarboxylic acid (6.5 mg, 0.058 mmol) and thionylchloride (0.8 mL, 11.0 mmol) was heated at 60° C. for 1.5 hr. The excessthionyl chloride was evaporated under vacuum. Residual thionyl chloridewas removed by adding toluene (1 mL) and concentrating the mixture todryness under vacuum. The residue was dissolved in CH₂Cl₂ (1.5 mL), andto the resulting solution was added the compound of Example 34, part B(20 mg, 0.049 mmol) in CH₂Cl₂ (1.5 mL), followed by the addition ofpyridine (0.080 mL, 0.99 mmol). The mixture was heated at reflux for 2hr before it was concentrated under vacuum. The residue was purifiedusing preparative HPLC to give the desired product (20.5 mg, 84% yield)as a pale yellow solid: LC/MS (M+H)⁺500.33.

EXAMPLE 50

This compound was prepared from the compound described in Example 3,part E using previously described coupling conditions: LC/MS(M+H)⁺=452.3.

A mixture of the compound from part A (112 mg, 0.25 mmol),(methoxycarbonylsulfamoyl)triethylammoniumhydroxide, inner salt (150 mg,0.63 mmol) and triethylamine (0.09 mL, 0.63 mmol) in THF (3 mL) wasstirred for 2 hr at rt. After partitioning the reaction mixture betweenEtOAc (25 mL) and water (25 mL), the organic layer was washed with water(25 mL) and brine (25 mL). The organic layer was dried over MgSO₄ andconcentrated to afford 88 mg (82%) of the titled compound as a whitesolid: LC/MS (M+H)⁺=436.37.

A mixture of the compound of part B (80 mg, 0.18 mmol) and tributyltinazide (150 mg, 0.45 mmol) in toluene (3 mL) was heated to 100° C. for 24hr. A supplemental amount of tributyltin azide (150 mg, 0.45 mmol) wasadded and the mixture was heated at 100° C. for 24 hr. The reactionmixture was loaded onto a 1×5 cm silica gel column, which was elutedwith 50 mL hexane, 50 mL of methylene chloride and 50 mL of 10%methanol/methylene chloride. Concentration of product containingfractions and trituration with ethyl ether afforded 12 mg (14%) of thetitled compound as a tan solid: LC/MS (M+H)⁺=479.37.

EXAMPLE 51

A mixture of the compound described in Example 3, part E (15 mg, 0.044mmol), methanesulfonamide (5 mg, 0.05 mmol), EDCI (10 mg, 0.05 mmol) and4-dimethylaminopyridine (7 mg, 0.055 mmol) in methylene chloride (0.5mL) was stirred 48 hr at rt. The reaction mixture was partitionedbetween EtOAc (5 mL) and saturated potassium bisulfate solution (5 mL).After washing with water (5 mL) and brine (5 mL), the organic layer wasdried over magnesium sulfate and concentrated to afford 11 mg (61%) ofthe titled compound as a white powder: MS (M+H)⁺=421.22.

EXAMPLES 52-455

Using methods similar to those previously described, the followingcompounds 52 through 455 were synthesized.

Ex. MS No. Structure (M + H)⁺ 52

555.08 53

441.4 54

445.04 55

525.21 56

551.12 57

493.3 58

524.32 59

539.28 60

580.38 61

567.16 62

485.34 63

479.37 64

540.14 65

540.53 66

499.45 67

594.36 68

554.31 69

513.27 70

626.45 71

640.32 72

599.29 73

573.28 74

612.46 75

574.38 76

624.39 77

510.43 78

510.34 79

541.35 80

582.42 81

554.98 82

583.37 83

597.36 84

568.47 85

582.32 86

610.35 87

569.18 88

583.29 89

551.11 90

603.97 91

475.4 92

491.57 93

504.58 94

489.6 95

489.58 96

543.52 97

491.28 98

519.5 99

595.19 100

493.38 101

465.29 102

452.12 103

516.2 104

544.32 105

568.28 106

598.18 107

596.35 108

626.54 109

568.26 110

608.5 111

564.43 112

594.51 113

608.46 114

634.26 115

610.58 116

580.26 117

596.58 118

608.19 119

594.34 120

623.47 121

579.35 22

581.36 123

607.51 124

584.18 125

582.4 126

566.39 127

585.22 128

585.17 129

596.65 130

596.59 131

470.4 132

580.26 133

594.4 134

644.4 135

644.35 136

568.24 137

568.43 138

598.18 139

610.26 140

610.24 141

630.35 142

580.4 143

623.26 144

622.43 145

644.28 146

644.2 147

630.19 148

598.19 149

598.2 150

634.3 151

634.32 152

594.34 153

600.22 154

552.3 155

610.31 156

608.3 157

582.26 158

582.24 159

596.35 160

604.38 161

660.12 162

614.11 163

566.27 164

624.27 165

624.18 166

524.14 167

582.17 168

510.09 169

610.49 170

583.21 171

525.14 172

585.18 173

571.19 174

566.22 175

581.24 176

511.12 177

580.29 178

727.23 179

593.28 180

622.36 181

622.32 182

551.25 183

567.23 184

583.26 185

576.42 186

598.24 187

608.31 188

584.16 189

607.33 190

580.35 191

590.23 192

610.27 193

475.3 194

530.37 195

471.12 196

525.19 197

549.19 198

539.53 199

484.25 200

498.19 201

638.39 202

624.54 203

638.48 204

622.33 205

632.34 206

662.22 207

582.19 208

612.35 209

612.34 210

568.19 211

527.19 212

485.1 213

514.97 214

484.06 215

614.32 216

526.23 217

614.2 218

514.25 219

528,25 220

611.31 221

535.31 222

503.25 223

586.37 224

579.26 225

593.35 226

597.43 227

597.33 228

607.21 229

583.57 230

500.33 231

572.33 232

572.34 233

558.34 234

379.39 235

364.1 236

365.06 237

529.19 238

447.21 239

461.33 240

511.17 241

502.17 242

532.19 243

483.24 244

421.22 245

489.20 246

504.14 247

518.22 248

590.21 249

511.15 250

490.21 251

488.14 252

625.28 253

611.30 254

651.19 255

651.17 256

612.14 257

612.14 258

419.2 259

420.22 260

441.3 261

483.4 262

454.3 263

439.4 264

535.3 265

483.4 266

499.4 267

453.4 268

516.4 269

407.3 270

453.4 271

441.4 272

456.4 273

511.5 274

535.4 275

567.3 276

524.3 277

441.4 278

507.3 279

409.3 280

427.3 281

441.4 282

483.4 283

530.4 284

462.4 285

453.4 286

502.4 287

452.3 288

545.4 289

487.4 290

513.3 291

554.2 292

534.3 293

559.4 294

566.4 295

501.1 296

498.4 297

535.2 298

491.4 299

499.2 300

543.3 301

491.4 302

495.4 303

477.4 304

473.3 305

410.3 306

486.2 307

449.2 308

431.3 309

468.4 310

397.3 311

425.3 312

411.3 313

425.3 314

452.4 315

429.4 316

571.1 317

521.4 318

442.2 319

500.4 320

468.4 321

517.1 322

453.4 323

441.4 324

598.1 325

488.3 326

489.3 327

591.6 328

589.3 329

453.3 330

413.16 331

512.21 332

499.14 333

475.2 334

453.22 335

443.38 336

558.22 337

597.52 338

443.24 339

597.37 340

611.47 341

371.24 342

399.29 343

427.32 344

415.31 345

401.34 346

456.35 347

412.19 348

397.59 349

438.59 350

516.45 351

477.44 352

495.01 353

535.98 354

470.09 355

455.07 356

537.29 357

537.33 358

471.05 359

471.44 360

486.42 361

541.08 362

525.12 363

555.11 364

539.34 365

524.94 366

496.92 367

534.01 368

492.99 369

484.07 370

514.13 371

499.12 372

514.06 373

500.33 374

584.12 375

599.18 376

470.05 377

484.09 378

535.96 379

440.1 380

443.06 381

485.36 382

514.07 383

512.19 384

468.13 385

471.16 386

500.1 387

515.28 388

533.21 389

514.29 390

584.34 391

598.36 392

625.42 393

619.38 394

585.12 395

599.13 396

558.1 397

583.11 398

586.28 499

608.27 400

627.3 401

641.34 402

598.29 403

542.25 404

470.1 405

586.25 406

611.17 407

599.62 408

639.29 409

570.23 410

597.25 411

585.24 412

626.31 413

441.3 414

524.34 415

493.34 416

551.35 417

533.33 418

576.35 419

436.37 420

444.34 421

554.35 422

430.32 423

479.37 424

540.32 425

527.09 426

513.5 427

457.06 428

443.49 429

457.44 430

467.30/ 469.30 431

443.31 432

612.18/ 614.18 433

569.42 434

541.4 435

473.45 436

618.06 437

569.4 438

583.4 439

555.1 440

555.1 441

567.29 442

638.31 443

570.3 444

571.28 445

557.33 446

585.39 447

571.27 448

598.15 449

498.19 450

540.19 451

433.56 452

475.27 453

533.56 454

465.59 455

507.24

1. A compound of formula I

diastereomers, enantiomers or salts thereof where Z is (1) —O—, (2) —S—,(3) —CR₄R₅—, (4) —CR₄R₅—O—CR_(4a)R_(5a)—, (5)—CR₄R₅—NR_(4b)—CR_(4a)R_(5a)—, or (6) —S—CR₄R₅—, R₁, R_(1b), R_(1ac) andR_(1ad) are independently (1) hydrogen or R₆, (2) —OH or —OR₆, (3)—C(O)_(q)H or —C(O)_(q)R₆, where q is 1 or 2, (4) halo, (5) -Z₄-NR₇R₈,R₂ and R₃ are each independently H or -Z₄-R_(6a); R₆, R_(6a), and R_(6b)are independently alkyl, cycloalkyl, aryl, or aralkyl, each of which isunsubstituted or substituted with Z₁, Z₂ and one or more groups Z₃; R₄,R_(4a), R_(4b), R₅ and R_(5a) are each independently hydrogen, alkyl,aryl, aralkyl, or cycloalkyl; R₇ and R₈ are each independently hydrogenor -Z₄R_(6b); Z₁ and Z₂ are each independently (1) hydrogen or Z₆, (2)—C(O)_(q)H or —C(O)_(q)Z₆, (3) -Z₄-NZ₇Z₈, where Z₄ is not a single bond,(4) -Z₄-N(Z₁₀)-Z₅-Z₆, where Z₄ is not a single bond, (5)-Z₄-N(Z₁₀)-Z₅-H, where Z₄ is not a single bond, (6) oxo; Z₃ is (1)hydrogen or Z₆, (2) —OH or —OZ₆, (3) —C(O)_(q)H or —C(O)_(q)Z₆, (4)halo, (5) -Z₄-NZ₇Z₈, (6) -Z₄-N(Z₁₀)-Z₅-Z₆, (7) -Z₄-N(Z₁₀)-Z₅-H, (8) oxo;Z₄ and Z₅ are independently (1) a single bond; (2) —(O)—; (3)—S(O)_(q)—; or (4) alkyl; Z₆ and Z_(6a) are independently (i) alkyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, or aralkyl; (ii) a group(i) which is itself substituted by one or more of the same or differentgroups (i); or (iii) a group (i) or (ii) which is independentlysubstituted by one or more of the groups (2) to (6) of the definition ofZ₁; Z₇, Z₈ and Z₁₀ are each independently hydrogen or -Z₄-Z_(6a).
 2. Acompound of formula I

diastereomers, enantionomers or salts thereof where Z is (1) —O—, (2)—S—, (3) —CR₄R₅—, (4) —S—CR₄R₅—, R₁, R_(1ab), R_(1ac) and R_(1ad) areindependently hydrogen, R₆ or —OR₆; R₂ and R₃ are each independently Hor -Z₄-R_(6a); R₆ and R_(6a) are independently alkyl, cycloalkyl, oraryl, each of which is unsubstituted or substituted with Z₁, Z₂ and oneor more groups Z₃; R₄ and R₅ are each independently hydrogen or alkyl;Z₁, Z₂ and Z₃ are each independently (1) hydrogen or Z₆, (2) —OH or—OZ₆, or (3) —C(O)_(q)H or —C(O)_(q)Z₆; Z₄ is (1) a single bond; or (2)—C(O)—; Z₆ and Z_(6a) are independently (i) alkyl, cycloalkyl, or aryl;(ii) a group (i) which is itself substituted by one or more of the sameor different groups (i); or (iii) a group (i) or (ii) which isindependently substituted by one or more of the groups (2) to (3) of thedefinition of Z₁.
 3. A compound of claim 2 where Z is (1) —S—, (2)—S—CR₄R₅—, R₁, R_(1ab), R_(1ac) and R_(1ad) are independently hydrogen,R₆ or —OR₆; R₂ and R₃ are each independently H or -Z₄-R_(6a); R₆ andR_(6a) are independently alkyl or aryl, each of which is unsubstitutedor substituted with Z₁, Z₂ and one or more groups Z₃; R₄ and R₅ are eachindependently hydrogen or alkyl; Z₁, Z₂ and Z₃ are each independently(1) hydrogen or Z₆, (2) —OH or —OZ₆, or (3) —C(O)_(q)H or —C(O)_(q)Z₆;Z₄is (1) a single bond; or (2) —C(O)—; Z₆ and Z_(6a) are independently(i) alkyl, cycloalkyl, or aryl; (ii) a group (i) which is itselfsubstituted by one or more of the same or different groups (i); or (iii)a group (i) or (ii) which is independently substituted by one or more ofthe groups (2) to (3) of the definition of Z₁.
 4. A compound of claim 3where Z is (1) —S—, (2) —S—CR₄R₅—, R₁, R_(1a), R_(1ac) and R_(1ad) areindependently hydrogen, R₆ or —OR₆; R₂ is H; R₃ is -Z₄-R_(6a); R₆ andR_(6a) are independently alkyl or aryl, each of which is unsubstitutedor substituted with Z₁, Z₂ and one or more groups Z₃; R₄ and R₅ are eachindependently hydrogen; Z₁, Z₂ and Z₃ are each independently hydrogen,Z₆ or —OZ₆; Z₄ is —C(O)—; Z₆ and Z_(6a) are independently alkyl,cycloalkyl, or aryl.
 5. A compound of claim 4 where Z is —S—, R_(6a) isaryl, which is unsubstituted or substituted with Z₁, Z₂ and one or moregroups Z₃; Z₁, Z₂ and Z₃ are each independently hydrogen, Z₆ or —OZ₆; Z₆is alkyl.
 6. A compound of claim 1 having the formula

wherein R₁, R₂, R₃, Z, R_(1ad), R_(1ab), R_(1ac), Z₁ and Z₂ are asdefined in claim
 1. 7. A compound of claim 6 where R₂ is H or alkyl; andR₃ is -Z₄-R_(6a), where: Z₄ is —C(O)— and R_(6a) is (1) aryl optionallysubstituted with one or more Z₁, Z₂ or Z₃; or (2) cycloalkyl optionallysubstituted with one or more Z₁, Z₂ or Z₃.
 8. A compound of claim 7wherein R₁, R_(1ab), R_(1ac) and R_(1ad) are independently H, alkyl,hydroxy, halo, —OR₆, or —NR₇R₈.
 9. A compound of claim 8 wherein atleast one of R_(1ab), R_(1ac) and R_(1ad) is other than H and Z₁ and Z₂are hydrogen.
 10. A compound of claim 6 having the following formula

where one of R_(1ab), R_(1ac) and R_(1ad) is H and the other two areindependently alkyl, hydroxy, halo, —OR₆, or —NR₇R₈.
 11. A compound ofclaim 10 wherein Z₁ and Z₂ are hydrogen and one of R_(1ab), R_(1ac) andR_(1ad) is H and the other two are independently alkyl or —OR₆.
 12. Acompound of claim 11 wherein Z is —S— and R_(1ac) is H.
 13. A compoundof claim 11 wherein Z is —S—CR₄R₅—, and R_(1ad) is H.
 14. A compound ofclaim 13 where R₄ and R₅ are hydrogen.
 15. A pharmaceutical compositioncomprising at least one compound of claim 1 and a pharmaceuticallyacceptable vehicle or carrier therefor.
 16. A pharmaceutical compositionof claim 15 further comprising at least one additional therapeutic agentselected from anti-inflammatory agents, anti-proliferative agents,anti-cancer agents or anti-cytotoxic agents.
 17. A pharmaceuticalcomposition of claim 16 wherein the additional therapeutic agents areselected from steroids, mycophenolate mofetil, LTD₄ inhibitors,CTLA4-Ig, LEA-29Y, phosphodiesterase inhibitors, antihistamines, or p³⁸MAPK inhibitors.